**Genetics of Posttraumatic Stress Disorder — Candidate Genes and Their Implication in the Disease-Associated Molecular Pathomechanisms**

Boyajyan Anna, Avetyan Diana, Hovhannisyan Lilit and Mkrtchyan Gohar

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60443

#### **Abstract**

[27] Feinstein, J.S., Buzza, C., Hurlemann, R., Follmer, R.L., Dahdaleh, N.S., Coryell, W.H., Welsh, M.J., Tranel, D., & Wemmie, J.A.: Fear and panic in humans with bilat‐

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[30] Targum, S.D. & Marshall, L.E.: Fenfluramine provocation of anxiety in patients with

[31] Ceulemans, D.L., Hoppenbrouwers, M.L., Gelders, Y.G., & Reyntjens, A.J.: The influ‐ ence of ritanserin, a serotonin antagonist, in anxiety disorders: a double-blind place‐

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[33] Magierek, V., Ramos, P.L., da Silveira-Filho, N.G., Nogueira, R.L., Landeira-Fernan‐ dez, J.: Context fear conditioning inhibits panic-like behavior elicited by electrical

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64 A Fresh Look at Anxiety Disorders

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Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder (DSM-V code: 309.81; ICD-10 codes: F43.1). PTSD is an anxiety disorder developed in a person experiencing, witnessing, or learning about an extreme physically or/and psycholog‐ ically distressing event. Its incidence and the number of this disease-affected people are threateningly increasing in contemporary society. Therefore, the development of prognostic strategies and novel efficient methods on early diagnostics and treatment of PTSD is currently considered as one of the most important healthcare problems worldwide.

Results of epidemiologic, clinical, and experimental studies suggest implication of both environmental and genetic factors in pathomechanisms of PTSD and that, most probably, PTSD belongs to complex disorders with polygenic inheritance. Whereas the environmental factors triggering PTSD are well defined, less is known about PTSD-associated genetic variations and molecular etiopathomechanisms.

Several studies, including our own reports, suggest the involvement of neuro-immune alterations in the pathophysiology of PTSD. These include changes in neuronal plasticity, synaptic connectivity, humoral and cellular immune-mediated responses, and apoptosis rate leading to cognitive deficit and behavioral changes in patients with PTSD accompanied with development of low-grade inflammatory reactions. Currently, many research groups working on elucidation of molecular mechanisms of PTSD are exploring whether these changes have genetic background or are induced by other external or internal environmental factors.

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In the present chapter, we provide overview and discussion of the existing data, including our own results, on variations in genes encoding neuro-immune and apoptotic mediators and regulators and related transcription factors in PTSD patients. Potential role of these genetic variations in generation and development of PTSD is considered and the implication of relevant candidate genes in mechanisms responsi‐ ble for disease progression is proposed.

**Keywords:** Apoptosis, candidate genes, complement system, posttraumatic stress dis‐ order, synaptic plasticity

### **1. Introduction**

Posttraumatic stress disorder (PTSD; DSM-V code: 309.81; ICD-10 codes: F43.1) is a complex, severe, and chronic psychiatric illness [1–2]. PTSD is an anxiety disorder developed in a person experiencing, witnessing, or learning about an extreme physically and/or psychologically distressing event [3–7]. Its incidence and the number of disease-affected people are threaten‐ ingly increasing in contemporary society. They usually remain out of society, become drug addicted, alcoholic, and often commit suicide [8–10]. Therefore, development of prognostic strategies, novel efficient methods on early diagnostics and treatment of PTSD is currently considered as one of the most important health care problems worldwide.

Results of epidemiologic, clinical, and experimental studies suggest implication of both environmental and genetic factors in pathomechanisms of PTSD, and that, most probably, PTSD belongs to the complex disorders with polygenic inheritance. PTSD is also unique in its exposure to an environmental (traumatic) event as the first criterion for diagnosis. Whereas the environmental factors triggering PTSD are well defined, less is known about PTSDassociated genetic variations and molecular etiopathomechanisms [11–17]. Although it is beyond the scope of many studies to comprehensively discuss the genetics of PTSD, it should be noted that there is an emerging literature on genetic variations in those neurobiological systems which drive responses to trauma and, consequently, are risk factors to develop PTSD. Many studies on detection of candidate genes association with PTSD are being carried up to date [18–26].

In the present chapter, we provide overview and discussion of the existing data, including genetic variants of serotonergic and dopaminergic systems, hypothalamic–pituitary–adrenal (HPA) axis, and other genes related to neurotransmission, neuromodulation, and stress physiology. Here, we have also included our own results on variations in genes encoding neuro, immune, and apoptotic mediators and regulators, and related transcription factors in PTSD patients. Potential role of these genetic variations in generation and development of PTSD is considered and the implication of relevant candidate genes in mechanisms responsible for disease progression is proposed.

### **2. Genetic Studies of PTSD**

In the present chapter, we provide overview and discussion of the existing data, including our own results, on variations in genes encoding neuro-immune and apoptotic mediators and regulators and related transcription factors in PTSD patients. Potential role of these genetic variations in generation and development of PTSD is considered and the implication of relevant candidate genes in mechanisms responsi‐

**Keywords:** Apoptosis, candidate genes, complement system, posttraumatic stress dis‐

Posttraumatic stress disorder (PTSD; DSM-V code: 309.81; ICD-10 codes: F43.1) is a complex, severe, and chronic psychiatric illness [1–2]. PTSD is an anxiety disorder developed in a person experiencing, witnessing, or learning about an extreme physically and/or psychologically distressing event [3–7]. Its incidence and the number of disease-affected people are threaten‐ ingly increasing in contemporary society. They usually remain out of society, become drug addicted, alcoholic, and often commit suicide [8–10]. Therefore, development of prognostic strategies, novel efficient methods on early diagnostics and treatment of PTSD is currently

Results of epidemiologic, clinical, and experimental studies suggest implication of both environmental and genetic factors in pathomechanisms of PTSD, and that, most probably, PTSD belongs to the complex disorders with polygenic inheritance. PTSD is also unique in its exposure to an environmental (traumatic) event as the first criterion for diagnosis. Whereas the environmental factors triggering PTSD are well defined, less is known about PTSDassociated genetic variations and molecular etiopathomechanisms [11–17]. Although it is beyond the scope of many studies to comprehensively discuss the genetics of PTSD, it should be noted that there is an emerging literature on genetic variations in those neurobiological systems which drive responses to trauma and, consequently, are risk factors to develop PTSD. Many studies on detection of candidate genes association with PTSD are being carried up to

In the present chapter, we provide overview and discussion of the existing data, including genetic variants of serotonergic and dopaminergic systems, hypothalamic–pituitary–adrenal (HPA) axis, and other genes related to neurotransmission, neuromodulation, and stress physiology. Here, we have also included our own results on variations in genes encoding neuro, immune, and apoptotic mediators and regulators, and related transcription factors in PTSD patients. Potential role of these genetic variations in generation and development of PTSD is considered and the implication of relevant candidate genes in mechanisms responsible

considered as one of the most important health care problems worldwide.

ble for disease progression is proposed.

order, synaptic plasticity

**1. Introduction**

66 A Fresh Look at Anxiety Disorders

date [18–26].

for disease progression is proposed.

#### **2.1. Neuroendocrine system candidate genes**

Many studies indicate association between PTSD and polymorphisms of number of genes, suggesting a polygenic nature of PTSD. Several studies indicate that functional abnormalities in neuroendocrine system detected in PTSD patients are conditioned with hereditary factor [21–26]. Thus, as it follows from Table 1, PTSD is associated with the genetic mutations in a number of genes encoding neurotransmitters, hormones and their enzymes, hormone receptors and transporters.



**Table 1.** Neuroendocrine system candidate genes in PTSD

#### *2.1.1. Dopaminergic system*

Dopaminergic system dysregulation has long been implicated in the pathophysiology of PTSD. A positive association between the risk for development of PTSD and Taq1A (rs1800497) polymorphism of the dopamine D2 receptor gene was found [24–30]. The dopamine D3 receptor (*DRD3*) gene's 4 SNPs (rs2134655, rs201252087, rs4646996, and rs9868039) showed evidence of association with PTSD [31]. Also, positive association was revealed between tandem repeat polymorphism of dopamine transporter gene and PTSD, as well as between dopamine D4 transporter gene long allele and severity of PTSD symptoms [32]. Recent publications reported that carriers of the 9R of allele of the gene, encoding the dopamine transporter (*SLC6A3, DAT, or DAT1*), had increased the risk of PTSD [33–36]. This finding suggests that genetically determined features of *DAT* may contribute to the development of PTSD among trauma survivors. Genetic variants in dopamine beta-hydroxylase (*DBH*) gene represent a likely candidate for examining genetic contributions to PTSD because of the role this enzyme plays in converting dopamine to norepinephrine as a part of catecholamine synthesis [37, 38]. A significant association between one or more copies of the rs4680 allele of *COMT* and PTSD has been reported. Thus, regulation of COMT and subsequent catecholamine neurotransmitter cascades may be an important factor in fear processing for those with PTSD and similar psychiatric disorders [39, 40]. Moreover, a recent study has shown a significant association of the *COMT* allele rs4633C with total PTSD, and severity scores of D category (negative alterations in cognitions and mood) of DSM-V categories [41].

#### *2.1.2. Serotonergic system candidate genes*

**Candidate genes Cytogenetic location Studied SNPs Source**

FK506 binding protein 5 *(FKBP5)* 6p21 rs9296158, rs3800373,

Apolipoprotein E *(ApoE)* 19q13 rs429358,

Brain-derived neurotrophic factor *(BDNF)* 11p14.1 rs6265 [30, 63-66]

Monoamine oxidase B *(MAOB)* Xp11.3 rs1799836 [70]

Regulator of G-protein signalling 2 *(RGS2)* 1q31.2 rs4606 [74]

Dopaminergic system dysregulation has long been implicated in the pathophysiology of PTSD. A positive association between the risk for development of PTSD and Taq1A (rs1800497) polymorphism of the dopamine D2 receptor gene was found [24–30]. The dopamine D3 receptor (*DRD3*) gene's 4 SNPs (rs2134655, rs201252087, rs4646996, and rs9868039) showed evidence of association with PTSD [31]. Also, positive association was revealed between tandem repeat polymorphism of dopamine transporter gene and PTSD, as well as between dopamine D4 transporter gene long allele and severity of PTSD symptoms [32]. Recent publications reported that carriers of the 9R of allele of the gene, encoding the dopamine transporter (*SLC6A3, DAT, or DAT1*), had increased the risk of PTSD [33–36]. This finding suggests that genetically determined features of *DAT* may contribute to the development of PTSD among trauma survivors. Genetic variants in dopamine beta-hydroxylase (*DBH*) gene represent a likely candidate for examining genetic contributions to PTSD because of the role this enzyme plays in converting dopamine to norepinephrine as a part of catecholamine synthesis [37, 38]. A significant association between one or more copies of the rs4680 allele of

5q31.3 rs41423247

rs258747

17q21.31 rs12944712 [53]

7p14.3 rs2267735 [54, 55]

rs7412

7p15.3 rs16139 [71]

10p12.1 rs6482463 [73]

1360780, rs9470080

[51, 52]

[56-62]

[67]

Glucocorticoid receptor GCCR *(NR3C1)*

68 A Fresh Look at Anxiety Disorders

*(ADCYAP1R1, PAC1)*

**Neurotrophic factor**

**Other genes**

Neuropeptide Y

protein 1 *(PRTFDC1)*

*2.1.1. Dopaminergic system*

*(NPY)*

*(CRHR1)*

Corticotropin-releasing hormone receptor-1

Phosphoribosyl transferase domain-containing

**Table 1.** Neuroendocrine system candidate genes in PTSD

Pituitary adenylate cyclase 1 receptor

Dysregulation of brain serotonergic systems has been implicated in the pathophysiology of PTSD; indeed, this pathway represents the most studied candidate in PTSD. The most studied polymorphism in this system is located in the promoter region of the serotonin transporter encoding gene (*SLC6A4, 5-HTTLPR*). Several studies indicated that this risk was associated with rs4795541, rs25531 genotypes, and PTSD [35, 42–45]. Serotonin receptor 2A rs6311 polymorphism has also been found to be associated with PTSD [46–47].

Goenjian and colleagues' studies have suggested association of *TPH1, TPH2*, and *5HTTLPR* with PTSD and depressive symptoms [48]. It was shown that the *TPH-2* allele rs11178997T and *COMT* allele rs4633C together accounted for 7% of the variance in severity scores of PTSD. Carriers of these *COMT* and *TPH-2* alleles may be at increased risk for PTSD. These findings provided biological support for dividing DSM-IV category C symptoms into DSM-V categories C and D [41].

#### *2.1.3. GABAergic system*

Inhibitory neurotransmitter, gamma-aminobutyric acid receptor gene (*GABAA*) has been studied in relation to PTSD. Three polymorphisms in the *GABAA* receptor subunit alpha 2 (*GABRA2*) had significant interactions with childhood trauma to predict PTSD [49].

#### *2.1.4. HPA axis candidate genes*

PTSD is also characterized by dysfunction of the stress response system, such that activity of the HPA axis is altered. Recent studies reported associations between PTSD and cannabinoid receptor (*CNR1*) gene variants NM\_016083 and NM\_033181; [50], glucocorticoid receptor (*NR3C1*, rs41423247, and rs258747) gene [51, 52], and between SNP in corticotropin-releasing hormone receptor-1 (*CRHR1*, rs12944712) and PTSD [53]. Also neuropeptide pituitary adenylate cyclase-activating polypeptide is regulating the stress response. Recently, a genetic variant in the PAC1 receptor (*ADCYAP1R1*; rs2267735) was found to be associated with PTSD [54, 55]. Of particular interest were the findings that a genetic variation of the glucocorticoid receptor cochaperone protein, FKBP5, moderates risk of developing PTSD in childhood abuse cases [56–61]. Binder and colleagues found that 4 SNPs in *FKBP5* (rs9296158, rs3800373, 1360780, rs9470080) interacted with child abuse severity to predict adult PTSD symptoms [62].

#### *2.1.5. Neurotrophic factor candidate genes*

Brain derived neurotrophic factor (BDNF) is involved in the neural plasticity underlying the extinction of fear and recovery from stress, both disrupted in PTSD. Based on its role in hippocampal-dependent learning and the neurobiology of anxiety and depression, the *BDNF* gene has been studied in relation to PTSD. A significant interaction between *DRD2* Taq1A (rs1800497) and Val66Met (rs6265) predicts PTSD severity [30]. Interestingly, a recent study in humans and rats suggested that *BDNF* overexpression may be a critical stress response underlying PTSD by showing that the Val66Met allele confers vulnerability to PTSD via startle data and plasma BDNF levels [63–66].

#### *2.1.6. Other candidate genes*

Apolipoprotein E (ApoE) is involved in stress dysregulation. A significant association between the ApoE2 allele and impaired memory and greater re-experiencing symptoms has been found in combat-exposed PTSD patients [67–69]. The monoamine oxidase B gene (*MAOB*) rs1799836 polymorphism has been studied in relation with PTSD because *MAOB* expression in platelets has been implicated in several psychopathologies and may represent a biomarker for vulner‐ ability to psychiatric illness [70]. Recent studies of the link between neuropeptide Y (NPY) and PTSD were published [71]. However, another study did not find any association between polymorphism in *NPY* (Leu7Pro; rs16139) and PTSD in a population of Caucasian combat veterans [72]. Nievergelt and colleagues found evidence for phosphoribosyl transferase domain-containing protein 1 (*PRTFDC1*) as a potential novel PTSD gene, but this finding needs further replication [73]. Finally, it was reported that the regulator of G-protein signaling 2 (RGS2) belongs to a protein family that has been widely involved in neural plasticity, partic‐ ularly associated with learning and memory, and may play a critical role in PTSD-associated cognitive dysfunction. In PTSD patients experiencing high stress and low social support, an association with *RGS2* (rs4606) was found [74].

#### **2.2. Complement system candidate genes**

The complement system is major effector of the immune response, which acts on the interface of innate and adaptive immunity, and is a key component and trigger of many immunoregu‐ latory mechanisms. Changes in the functional activity of the complement cascade contribute to the pathology of many human diseases [75–77], including mental disorders [78–83], and are also detected during physiological stress [84, 85]. It has already been demonstrated that complement system alterations are involved in PTSD pathogeneses, particularly hypoactiva‐ tion state of the complement alternative pathway in PTSD patients, which positively and significantly correlates (p < 0.05) with total (frequency and intensity) PTSD symptom cluster of re-experiencing, avoidance, and hyperarousal, and with PTSD total symptom score [13]. Now, our interest is focused on studying the genetic basis of complement system regulators, particularly the role and genetic variants of complement factors B, H, and I (*CFB, CFH*, and *CFI*, accordingly) in PTSD. The distributions of genotypes for *CFB, CFH*, and *CFI* SNPs in both patients and control groups were in compliance with Hardy–Weinberg equilibrium (*p* > 0.05). The allele and phenotype frequencies of *CFB, CFH*, and *CFI* genetic variants in the groups of PTSD patients and controls are shown in Table 2.


hippocampal-dependent learning and the neurobiology of anxiety and depression, the *BDNF* gene has been studied in relation to PTSD. A significant interaction between *DRD2* Taq1A (rs1800497) and Val66Met (rs6265) predicts PTSD severity [30]. Interestingly, a recent study in humans and rats suggested that *BDNF* overexpression may be a critical stress response underlying PTSD by showing that the Val66Met allele confers vulnerability to PTSD via startle

Apolipoprotein E (ApoE) is involved in stress dysregulation. A significant association between the ApoE2 allele and impaired memory and greater re-experiencing symptoms has been found in combat-exposed PTSD patients [67–69]. The monoamine oxidase B gene (*MAOB*) rs1799836 polymorphism has been studied in relation with PTSD because *MAOB* expression in platelets has been implicated in several psychopathologies and may represent a biomarker for vulner‐ ability to psychiatric illness [70]. Recent studies of the link between neuropeptide Y (NPY) and PTSD were published [71]. However, another study did not find any association between polymorphism in *NPY* (Leu7Pro; rs16139) and PTSD in a population of Caucasian combat veterans [72]. Nievergelt and colleagues found evidence for phosphoribosyl transferase domain-containing protein 1 (*PRTFDC1*) as a potential novel PTSD gene, but this finding needs further replication [73]. Finally, it was reported that the regulator of G-protein signaling 2 (RGS2) belongs to a protein family that has been widely involved in neural plasticity, partic‐ ularly associated with learning and memory, and may play a critical role in PTSD-associated cognitive dysfunction. In PTSD patients experiencing high stress and low social support, an

The complement system is major effector of the immune response, which acts on the interface of innate and adaptive immunity, and is a key component and trigger of many immunoregu‐ latory mechanisms. Changes in the functional activity of the complement cascade contribute to the pathology of many human diseases [75–77], including mental disorders [78–83], and are also detected during physiological stress [84, 85]. It has already been demonstrated that complement system alterations are involved in PTSD pathogeneses, particularly hypoactiva‐ tion state of the complement alternative pathway in PTSD patients, which positively and significantly correlates (p < 0.05) with total (frequency and intensity) PTSD symptom cluster of re-experiencing, avoidance, and hyperarousal, and with PTSD total symptom score [13]. Now, our interest is focused on studying the genetic basis of complement system regulators, particularly the role and genetic variants of complement factors B, H, and I (*CFB, CFH*, and *CFI*, accordingly) in PTSD. The distributions of genotypes for *CFB, CFH*, and *CFI* SNPs in both patients and control groups were in compliance with Hardy–Weinberg equilibrium (*p* > 0.05). The allele and phenotype frequencies of *CFB, CFH*, and *CFI* genetic variants in the groups of

data and plasma BDNF levels [63–66].

association with *RGS2* (rs4606) was found [74].

PTSD patients and controls are shown in Table 2.

**2.2. Complement system candidate genes**

*2.1.6. Other candidate genes*

70 A Fresh Look at Anxiety Disorders


a pcorrected values for comparison of mutant allele frequency between PTSD patients and controls.

b pcorrected values for comparison of mutant allele carriage between PTSD patients and controls.

**Table 2.** Distribution of genotypes, alleles and carriage of minor alleles of CFB, CFH and CFI polymorphisms in patients with PTSD and controls.

According to the results obtained, the *CFI* rs1000954\*A allele was more frequent in controls than in patients (0.29 vs. 0.20, *p*nominal = 0.008, OR = 0.61, 95 %CI: 0.42-0.88). Also, the carriers of this allele were overrepresented in the group of controls compared to patients (0.51 vs. 0.34, *p*nominal = 0.002, OR = 2.03, 95% CI: 1.29–3.2). In case of other selected polymorphisms, no significant association with PTSD was found (*p* > 0.05).

#### **2.3. Candidate genes of apoptosis**

Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli [86]. According to various apoptotic stimuli, apoptosis can be induced by two major pathways: the intrinsic pathway (mitochondria-dependent pathway) and the extrinsic pathway (death receptor-dependent pathway) [87]. Recent studies reported that neuronal apoptosis of amygdala, hippocampus, and medial prefrontal cortex (mPFC) have a certain relationship with the pathogenesis of PTSD [88]. However, the role of apoptosis in the pathogenesis of PTSD is not yet entirely clear.

Apoptosis is the process of strict control multigene, known in the process of apoptosis with a series of apoptosis-related genes, such as Bcl-2 family, caspase family, C-myc oncogenes, and tumor suppressor gene P53, etc. The Bcl-2 family proteins play a crucial role in the process of apoptosis and are considered to be the final passage of apoptosis. Bcl-2 family proteins regulate mitochondrial structure and functional stability with the help of other apoptosis protein synergy. According to the recent study, the increase of the Bcl-2 and Bax expression and the imbalance in the Bcl-2/Bax ratio were few of the mechanisms causing mPFC neuronal apop‐ tosis, which may be one of the reasons of PTSD development in rat [88].

**Gene (SNP) Genotypes Alleles Carriage** p 0.089 0.279 OR 1.29 0.77 95% CI: 0.962-1.73 0.486-1.23

*CFI***rs1000954** GG GA AA G A A PTSD 98 (0.66) 40 (0.27) 10 (0.07) 236 (0.8) 60 (0.2) 50 (0.34) Controls 84 (0.488) 75 (0.436) 12 (0.076) 243 (0.71) 101 (0.29) 87 (0.51) p **0.02a 0.006b** OR 0.61 2.03 95% CI: 0.42-0.88 1.29-3.2 *CFI* **rs4469075** CC CG GG C G G PTSD 19 (0.13) 60 (0.42) 65 (0.45) 98 (0.34) 190 (0.66) 79 (0.55) Controls 17 (0.1) 76 (0.5) 71 (0.4) 110 (0.3) 218 (0.7) 93 (0.57) p 1.0 0.75 OR 0.98 1.32 95% CI: 0.7-1.37 0.64– 2.70

pcorrected values for comparison of mutant allele frequency between PTSD patients and controls.

pcorrected values for comparison of mutant allele carriage between PTSD patients and controls.

significant association with PTSD was found (*p* > 0.05).

**Table 2.** Distribution of genotypes, alleles and carriage of minor alleles of CFB, CFH and CFI polymorphisms in

According to the results obtained, the *CFI* rs1000954\*A allele was more frequent in controls than in patients (0.29 vs. 0.20, *p*nominal = 0.008, OR = 0.61, 95 %CI: 0.42-0.88). Also, the carriers of this allele were overrepresented in the group of controls compared to patients (0.51 vs. 0.34, *p*nominal = 0.002, OR = 2.03, 95% CI: 1.29–3.2). In case of other selected polymorphisms, no

Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli [86]. According to various apoptotic stimuli, apoptosis can be induced by two major pathways: the intrinsic pathway (mitochondria-dependent pathway) and the extrinsic pathway (death receptor-dependent pathway) [87]. Recent studies reported that neuronal apoptosis of amygdala, hippocampus, and medial prefrontal cortex (mPFC) have a certain relationship with the pathogenesis of PTSD [88]. However, the role of apoptosis in the pathogenesis of PTSD is not yet entirely clear.

Apoptosis is the process of strict control multigene, known in the process of apoptosis with a series of apoptosis-related genes, such as Bcl-2 family, caspase family, C-myc oncogenes, and

a

b

patients with PTSD and controls.

72 A Fresh Look at Anxiety Disorders

**2.3. Candidate genes of apoptosis**

According to our study, the rs956572\*A minor allele of the *BCL2* gene was overrepresented in patients with PTSDcompared to healthy subjects (0.64 vs. 0.41, *p*nominal = 6.02E-11,OR= 2.59, 95% CI: 1.94–3.44). In addition, the carriers of this allele were more in the group of patients com‐ pared to controls (0.87 vs. 0.65, *p*nominal = 4.11E-7, OR= 3.53, 95% CI: 2.14–5.81). Further, we found that the rs1801018\*G minor allele of the *BCL2* gene was more frequent among controls com‐ pared to patients (0.5 vs. 0.4, *p*nominal = 0.0036, OR = 0.66, 95% CI: 0.50–0.87). Also, the carriers of the rs1801018\*Gminor alleleweremore frequentincontrols thaninpatients (0.79vs. 0.61, *p*nominal = 8.6E-5, OR = 2.41, 95% CI: 1.54–3.75). After Bonferroni correction, difference in allele frequen‐ cy between the patient and the control groups minor alleles remained significant (Table 3).



a pcorrected values for comparison of mutant allele frequency between PTSD patients and controls.

b pcorrected values for comparison of mutant allele carriage between PTSD patients and controls.

**Table 3.** Distribution of genotypes, alleles and carriage of minor alleles of *ANXA5, ANXA11* and *BCL2* polymorphisms in patients with PTSD and controls.

The externalization of phosphatidylserine is one of the leading indicators of apoptosis. The annexins are multigene family of Ca2+-regulated phospholipid-dependent and membranebinding annexin proteins [89]. One member of the annexin gene family, annexin A5, is known as a Ca2+-dependent, phospholipid-binding protein that inhibits protein kinase C (PKC) signaling. Although annexin A5 has been used for the detection of apoptosis, it shows high affinity for surface-exposed phosphatidylserine during apoptosis and may directly involve in apoptotic pathway [90]. Another member of annexins family is annexin A11, which is involved in calcium signaling, apoptosis, vesicle trafficking, cell growth, and the terminal phase of cell division [91].

According to the results obtained, the blood level of annexin-А5 was significantly lower in PTSD and which may also be one of the factors responsible for development of PTSDassociated low-grade inflammation [92, 93]. The results of annexin family proteins encoding genes association with PTSD are shown in Table 3. The *ANXA11* gene rs1049550\*A allele was more frequent among controls than in patients (0.42 vs. 0.33, *p*nominal = 0.013, OR = 0.695, 95% CI: 0.52–0.93). There were no significant differences of carriers of rs1049550\*A minor allele in the group of patients compared to controls.

#### **2.4. Candidate genes of synaptic plasticity**

Synaptic plasticity change, which is a fundamental characteristic of the nervous system, underlies numerous aspects of cognition. Plasticity is essential for the recovery of the nervous system after injury, stroke, and other pathological processes and can permit remarkable functional recovery even after devastating damage, especially in a young and otherwise healthy brain. However, the very mechanisms of plasticity that permit development, learning, resilience, memory, and recovery can also contribute to behavioral dysfunction and to psychopathology [94].

Complexins are small, cytosolic proteins that bind to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex to regulate synaptic vesicle exocytosis. Complexin 1 and 2 are the two major isoforms in the brain [95, 96]. Significant alterations of complexins 2 expression levels are seen in a number of neurological and psychiatric disorders, including bipolar disorder [97–99], major depression [98, 100], Huntington's disease (HD) [101, 102], schizophrenia [97, 100, 103–107], Parkinson's disease [108], Alzheimer's disease [109], and PTSD [93].

**Gene (SNP) Genotypes Alleles Carriage** PTSD 78 (0.39) 83 (0.415) 39 (0.195) 239 (0.6) 161 (0.4) 122 (0.61) Controls 42 (0.21) 114 (0.57) 44 (0.22) 198 (0.5) 202 (0.5) 158 (0.79) p **0.0072a 0.00017b** OR 0.66 2.41 95% CI: 0.5 - 0.87 1.54 - 3.75

**Table 3.** Distribution of genotypes, alleles and carriage of minor alleles of *ANXA5, ANXA11* and *BCL2* polymorphisms

The externalization of phosphatidylserine is one of the leading indicators of apoptosis. The annexins are multigene family of Ca2+-regulated phospholipid-dependent and membranebinding annexin proteins [89]. One member of the annexin gene family, annexin A5, is known as a Ca2+-dependent, phospholipid-binding protein that inhibits protein kinase C (PKC) signaling. Although annexin A5 has been used for the detection of apoptosis, it shows high affinity for surface-exposed phosphatidylserine during apoptosis and may directly involve in apoptotic pathway [90]. Another member of annexins family is annexin A11, which is involved in calcium signaling, apoptosis, vesicle trafficking, cell growth, and the terminal phase of cell

According to the results obtained, the blood level of annexin-А5 was significantly lower in PTSD and which may also be one of the factors responsible for development of PTSDassociated low-grade inflammation [92, 93]. The results of annexin family proteins encoding genes association with PTSD are shown in Table 3. The *ANXA11* gene rs1049550\*A allele was more frequent among controls than in patients (0.42 vs. 0.33, *p*nominal = 0.013, OR = 0.695, 95% CI: 0.52–0.93). There were no significant differences of carriers of rs1049550\*A minor allele in

Synaptic plasticity change, which is a fundamental characteristic of the nervous system, underlies numerous aspects of cognition. Plasticity is essential for the recovery of the nervous system after injury, stroke, and other pathological processes and can permit remarkable functional recovery even after devastating damage, especially in a young and otherwise healthy brain. However, the very mechanisms of plasticity that permit development, learning, resilience, memory, and recovery can also contribute to behavioral dysfunction and to

Complexins are small, cytosolic proteins that bind to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex to regulate synaptic vesicle exocytosis. Complexin 1 and 2 are the two major isoforms in the brain [95, 96]. Significant alterations of

pcorrected values for comparison of mutant allele frequency between PTSD patients and controls.

pcorrected values for comparison of mutant allele carriage between PTSD patients and controls.

a

b

in patients with PTSD and controls.

74 A Fresh Look at Anxiety Disorders

the group of patients compared to controls.

**2.4. Candidate genes of synaptic plasticity**

psychopathology [94].

division [91].

Neurotrophin family are traditionally recognized for their nerve growth promoting function and are recently identified as crucial factors in regulating neuronal activity in the central and peripheral nervous systems. The family members including brain-derived neurotrophic factor (*BDNF*), nerve growth factor (*NGF*), and its receptor (*NGFR*) are the essential mediators of synaptic and morphological plasticity, neuronal growth, survival, and differentiation; especially in the developing brain, thought may play an important role in pathogenesis of PTSD. [110]

We have reviewed data related neurotransmitter/neuroendocrine systems that are known to be involved in the pathophysiology of PTSD and that may contribute to the symptoms and cognitive dysfunctions in these patients. In Table 4, we have collected our data concerning candidate genes of the proteins involved in synaptic plasticity which may contribute to PTSD.




**Gene (SNP) Genotypes Alleles Carriage** Controls 36 (0.34) 43 (0.41) 26 (0.25) 115 (0.55) 95 (0.45) 69 (0.66) p 0.2a 0.8b OR 0.79 1.06 95% CI: 0.55 – 1.14 0.62 - 1.82

76 A Fresh Look at Anxiety Disorders

*NGF* **rs6330** CC CT TT C T T

*NGFR* **rs734194** CC CT TT C T T PTSD 164 (0.82) 34 (0.17) 2 (0.01) 362 (0.9) 38 (0.1) 36 (0.18) Controls 109 (0.545) 74 (0.37) 17 (0.085) 292 (0.73) 108 (0.27) 91 (0.46) p **2.74E-10a 8.82E-09b** OR 0.284 0.263 95% CI: 0.19 - 0.42 0.17 - 0.42

*CHN1* **rs14228** CC CT TT C T T PTSD 79 (0.395) 86 (0.43) 35 (0.175) 244 (0.61) 156 (0.39) 121 (0.6) Controls 82 (0.41) 62 (0.31) 56 (0.28) 226 (0.565) 174 (0.435) 118 (0.59) p 0.39a 1.52b OR 0.83 0.94 95% CI: 0.63 - 1.1 0.63 - 1.4

PTSD 66 (0.33) 106 (0.53) 28 (0.14) 238 (0.6) 162 (0.4) 134 (0.67) Controls 130 (0.65) 58 (0.29) 12 (0.06) 318 (0.8) 82 (0.2) 70 (0.35) p **2.04E-09a 4.20E-10b** OR 2.64 3.77 95% CI: 1.9 - 3.6 2.5 - 5.7 *NGF* **rs4839435** GG GA AA G A A PTSD 130 (0.65) 66 (0.33) 4 (0.02) 326 (0.8) 74 (0.2) 70 (0.35) Controls 85 (0.425) 97 (0.485) 18 (0.09) 267 (0.67) 133 (0.33) 115 (0.58) p **4.00E-06a 1.20E-05b** OR 0.46 0.4 95% CI: 0.33 - 0.63 0.27 - 0.6 *NGFR* **rs11466155** CC CT TT C T T PTSD 109 (0.545) 82 (0.41) 9 (0.045) 300 (0.75) 100 (0.25) 91 (0.46) Controls 110 (0.55) 75 (0.375) 15 (0.075) 295 (0.74) 105 (0.26) 90 (0.45) p 1.37a 2b OR 0.94 0.98 95% CI: 0.68 - 1.29 0.66 - 1.45

> a pcorrected values for comparison of mutant allele frequency between PTSD patients and controls.

b pcorrected values for comparison of mutant allele carriage between PTSD patients and controls.

**Table 4.** Distribution of genotypes, alleles and carriage of minor alleles of *BDNF, CPLX2, NTNG1, NGF, NGFR, CHN1, FOS, JUN*and *IER5* polymorphisms in patients with PTSD and controls.

According to the data obtained, the rs6265\*A allele of the*BDNF* gene was more frequent in controls than in patients (0.19 vs. 0.13, *p*nominal = 0.03, OR = 0.65, 95% CI: 0.44–0.95). Also, the carriers of rs6265\*A minor allele were overrepresented in the group of controls compared to patients (0.36 vs. 0.25, *p*nominal = 0.02, OR = 1.65, 95% CI: 1.07–2.54). In contrast, the rs1366116\*T minor allele of the *CPLX2* gene was more frequent among patients compared to controls (0.4 vs. 0.24, *p*nominal = 0.002, OR = 2.2, 95% CI: 1.4–3.6). Also, the carriers of this allele were more in the group of patients compared to controls (0.61 vs. 0.4, *p*nominal = 0.008, OR = 0.43, 95% CI: 0.2– 0.8). Further, we found that the rs6330\*T allele of the *NGF* gene was overrepresented in patients with PTSD compared to healthy subjects (0.4 vs. 0.2, *p*nominal = 1.02E-9, OR = 2.64, 95% CI: 1.93– 3.61). Also, the carriers of the rs6330\*T minor allele (CT + TT) were more frequent in patients than in controls (0.67 vs. 0.35, *p*nominal = 2.1E-10, OR = 3.77, 95% CI: 2.49–5.70). On the contrary, the frequency (0.33 vs. 0.2, *p*nominal = 2.0E-6, OR = 0.46, 95% CI: 0.33–0.63) and carriers (0.58 vs. 0.35, *p*nominal = 6.0E-6, OR = 0.40, 95% CI: 0.27–0.60) of the rs4839435\*A minor allele of the *NGF* gene were higher in controls than in PTSD patients. The *NGFR* rs734194\*T minor allele frequency again was higher in controls than in patients (0.27 vs. 0.1, *p*nominal = 1.37E-10, OR = 0.28, 95% CI: 0.19–0.42). The same applies to the carriers of the *NGFR* rs734194\*T allele (0.46 vs. 0.18, *p*nominal = 4.41E-9, OR = 0.26, 95% CI: 0.17–0.42). Also, rs7101\*T allele of the *FOS* gene was more frequent in patients than in controls (0.76 vs. 0.31, *p*nominal = 2.02E-37, OR = 6.90, 95% CI: 5.05–9.43). The carriers of rs7101\*T minor allele were overrepresented in the group of patients compared to controls (0.94 vs. 0.53, *p*nominal = 6.57E-22, OR = 13.89, 95% CI: 7.28–26.51). In contrast, the rs1063169\*T minor allele of the *FOS* gene was more frequent among controls compared to patients (0.34 vs. 0.1, *p*nominal = 7.48E-16, OR = 0.23, 95% CI: 0.16–0.33). Also, the carriers of this allele were more in the group of controls compared to patients (0.54 vs. 0.2, *p*nominal = 8.51E-13, OR = 0.21, 95% CI: 0.13–0.32). After Bonferroni correction, difference in allele frequency between the patient and the control groups for these minor alleles remained significant.

### **3. Conclusion**

As found in several mental disorders, the risk for PTSD following traumatic event has limited genetic heritability. The genetic understanding of PTSD through candidate gene studies is premature at this point, although several genes hold promise as potential biomarkers. Identifying and understanding the genetics of PTSD will enrich our ability of diagnosis of PTSD. In Figure 1, we summarized the candidate genes responsible for generation and development of PTSD.

Several studies indicated the association between PTSD and polymorphisms of number of genes of dopaminergic, serotonergic, and GABAergic systems, HPA axis, and other genes related to neurotransmission, neuromodulation, etc. We also compiled a list of genes that have been reported in the literature to be significantly associated with PTSD, also adding our own results on variations in genes encoding neuro-, immune and apoptotic mediators and regula‐ tors, and related transcription factors. Profound understanding of risks in PTSD is possible through classic and convergent genomic approaches and this will lead to development of

Genetics of Posttraumatic Stress Disorder — Candidate Genes and Their Implication… http://dx.doi.org/10.5772/60443 79

**Figure 1.** Candidate genes responsible for development of PTSD.

targeted treatment and prevention approaches. Overall, such researches highlight the potential usefulness of the assessment of target genes' alteration in diagnosis of PTSD.

#### **Author details**

According to the data obtained, the rs6265\*A allele of the*BDNF* gene was more frequent in controls than in patients (0.19 vs. 0.13, *p*nominal = 0.03, OR = 0.65, 95% CI: 0.44–0.95). Also, the carriers of rs6265\*A minor allele were overrepresented in the group of controls compared to patients (0.36 vs. 0.25, *p*nominal = 0.02, OR = 1.65, 95% CI: 1.07–2.54). In contrast, the rs1366116\*T minor allele of the *CPLX2* gene was more frequent among patients compared to controls (0.4 vs. 0.24, *p*nominal = 0.002, OR = 2.2, 95% CI: 1.4–3.6). Also, the carriers of this allele were more in the group of patients compared to controls (0.61 vs. 0.4, *p*nominal = 0.008, OR = 0.43, 95% CI: 0.2– 0.8). Further, we found that the rs6330\*T allele of the *NGF* gene was overrepresented in patients with PTSD compared to healthy subjects (0.4 vs. 0.2, *p*nominal = 1.02E-9, OR = 2.64, 95% CI: 1.93– 3.61). Also, the carriers of the rs6330\*T minor allele (CT + TT) were more frequent in patients than in controls (0.67 vs. 0.35, *p*nominal = 2.1E-10, OR = 3.77, 95% CI: 2.49–5.70). On the contrary, the frequency (0.33 vs. 0.2, *p*nominal = 2.0E-6, OR = 0.46, 95% CI: 0.33–0.63) and carriers (0.58 vs. 0.35, *p*nominal = 6.0E-6, OR = 0.40, 95% CI: 0.27–0.60) of the rs4839435\*A minor allele of the *NGF* gene were higher in controls than in PTSD patients. The *NGFR* rs734194\*T minor allele frequency again was higher in controls than in patients (0.27 vs. 0.1, *p*nominal = 1.37E-10, OR = 0.28, 95% CI: 0.19–0.42). The same applies to the carriers of the *NGFR* rs734194\*T allele (0.46 vs. 0.18, *p*nominal = 4.41E-9, OR = 0.26, 95% CI: 0.17–0.42). Also, rs7101\*T allele of the *FOS* gene was more frequent in patients than in controls (0.76 vs. 0.31, *p*nominal = 2.02E-37, OR = 6.90, 95% CI: 5.05–9.43). The carriers of rs7101\*T minor allele were overrepresented in the group of patients compared to controls (0.94 vs. 0.53, *p*nominal = 6.57E-22, OR = 13.89, 95% CI: 7.28–26.51). In contrast, the rs1063169\*T minor allele of the *FOS* gene was more frequent among controls compared to patients (0.34 vs. 0.1, *p*nominal = 7.48E-16, OR = 0.23, 95% CI: 0.16–0.33). Also, the carriers of this allele were more in the group of controls compared to patients (0.54 vs. 0.2, *p*nominal = 8.51E-13, OR = 0.21, 95% CI: 0.13–0.32). After Bonferroni correction, difference in allele frequency between the patient and the control groups for these minor alleles remained

As found in several mental disorders, the risk for PTSD following traumatic event has limited genetic heritability. The genetic understanding of PTSD through candidate gene studies is premature at this point, although several genes hold promise as potential biomarkers. Identifying and understanding the genetics of PTSD will enrich our ability of diagnosis of PTSD. In Figure 1, we summarized the candidate genes responsible for generation and

Several studies indicated the association between PTSD and polymorphisms of number of genes of dopaminergic, serotonergic, and GABAergic systems, HPA axis, and other genes related to neurotransmission, neuromodulation, etc. We also compiled a list of genes that have been reported in the literature to be significantly associated with PTSD, also adding our own results on variations in genes encoding neuro-, immune and apoptotic mediators and regula‐ tors, and related transcription factors. Profound understanding of risks in PTSD is possible through classic and convergent genomic approaches and this will lead to development of

significant.

**3. Conclusion**

78 A Fresh Look at Anxiety Disorders

development of PTSD.

Boyajyan Anna, Avetyan Diana, Hovhannisyan Lilit and Mkrtchyan Gohar\*

\*Address all correspondence to: g\_mkrtchyan@mb.sci.am

Institute of Molecular Biology, National Academy of Sciences, Yerevan, Republic of Armenia

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## **Posttraumatic Stress Disorder Biomarker — p11**

Lei Zhang, Xian-Zhang Hu, He Li, Xiaoxia Li, Stanley Smerin, Dale W. Russell, Angela Boutte, Berwin Yuan, Nora Wang, Ze Chen and Robert J. Ursano

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/61073

#### **Abstract**

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88 A Fresh Look at Anxiety Disorders

Post-traumatic stress disorder (PTSD) is a chronic and disabling anxiety disorder associated with a traumatic event [1]. It is linked to increased risk of suicide and deficits in social functioning [2, 3]. Despite extensive study in psychiatry, the underlying mechanisms of PTSD are still poorly understood [4, 5]. Currently, the diagnosis for PTSD is based on clinical observation and symptom checklist [4, 6-8] and no laboratory blood-based tests. Although biomarker discovery for PTSD is not easy [8], a reliable biomarker would significantly impact the diagnosis and therapeutic monitoring of PTSD. Developing interventions to identify and treat PTSD requires objective approaches to determining the presence of PTSD [8]. Substantial data indicate several potential biomarkers for PTSD. Of these candidate markers, p11 (S100A10) has been studied in PTSD animal models [7] and in human subjects with PTSD [6]. We found that p11 is over-expressed in both animal models and postmortem brains of subjects with PTSD [7]. Incorporating testing of p11, a novel biomarker for PTSD, into clinical practice, along with more subjective measures, such as participants' medical history, mental status, duration of symptoms, and symptom checklist or self-report, would provide additional power to predict impending PTSD. In this chapter, we discuss the biomarker concept and the potential clinical utility of PTSD biomarkers. We further discuss the potential of p11 as a PTSD biomarker and as a tool that may enhance PTSD diagnosis and intervention in health care practice.

**Keywords:** PTSD, p11, biomarker

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1. Introduction**

Post-traumatic stress disorder (PTSD) is a chronic and disabling anxiety disorder which is a result of exposure to a traumatic event and is associated with an increased risk of suicide and marked deficits in social dysfunction [2, 3]. Currently, a PTSD diagnosis is made based on clinical observation, symptoms, and the duration of symptoms. In 2013, the American Psychiatric Association's *Fifth Edition of the Diagnostic and Statistical Manual of Mental Disor‐ ders* (DSM-5) revised PTSD diagnostic criteria to better codify it to adults, adolescents, and children over age six. The criteria currently include exposure to a traumatic event and symptoms of four symptom clusters: intrusion, avoidance, negative alterations in cognitions and mood, and alterations in arousal and reactivity. Additional criteria include the duration of symptoms [9]. Given that there are currently no laboratory biomarker tests for PTSD, this chapter will discuss the concept of using biomarkers to diagnose the potential for the existence of PTSD. Specific focus will be given to the potential of biomarker p11.

### **2. Biomarker concept**

Biomarkers are defined as "cellular, biochemical, or molecular alterations that are measurable in biological media such as human tissues, cells, or fluids" [10-12]. Biomarkers can be meas‐ urable and quantifiable biological parameters, such as levels of protein or enzyme and hormone in the cerebrospinal fluid, saliva and blood, or mRNA specimen levels [10-12]. Those markers may be related to health and physiological conditions, metabolic processes, disease risk, psychiatric disorders, and environmental exposure, as well as disease diagnosis [13]. Biological changes, which link mechanism of drug action to clinical effectiveness, are also considered biomarkers [14]. Therefore, biomarkers may be considered as any substance, structure of molecule, or biological process that are measurable, influential and/or able to predict the incidence of outcome of disease (WHO International Program on Chemical Safety).

### **3. Biomarker classification and application**

Biomarker research has advanced substantially as part of the Human Genome Project [15]. Initially, potential gene biomarkers were screened using high-throughput analytical instru‐ ments. Those markers were classified into four subgroups: type 0 biomarkers; type 1 biomark‐ ers; surrogate end point-type (type 2 biomarkers); and risk markers (http://en.wikipedia.org/ wiki/Human\_Genome\_Project). Depending on the function of those markers, they may be called imaging biomarkers (CT, PET, MRI), molecular biomarkers, or genetic markers. Molecular biomarkers include the markers in biological specimens (plasma, serum, saliva, cerebrospinal fluid, bronchoalveolar lavage, and biopsy). They can be peptides, proteins, lipids metabolites, enzymes, and other small molecules (http://en.wikipedia.org/wiki/ Human\_Genome\_Project). Genetic markers are micromRNA, mRNA and DNA mutations, or polymorphisms. Finally, these markers may also be used for diagnosing the disease, deter‐ mining the stage of the disease, monitoring the outcome of the treatment, and evaluating the disease prognosis.

### **4. Potential PTSD biomarkers**

**1. Introduction**

90 A Fresh Look at Anxiety Disorders

**2. Biomarker concept**

Post-traumatic stress disorder (PTSD) is a chronic and disabling anxiety disorder which is a result of exposure to a traumatic event and is associated with an increased risk of suicide and marked deficits in social dysfunction [2, 3]. Currently, a PTSD diagnosis is made based on clinical observation, symptoms, and the duration of symptoms. In 2013, the American Psychiatric Association's *Fifth Edition of the Diagnostic and Statistical Manual of Mental Disor‐ ders* (DSM-5) revised PTSD diagnostic criteria to better codify it to adults, adolescents, and children over age six. The criteria currently include exposure to a traumatic event and symptoms of four symptom clusters: intrusion, avoidance, negative alterations in cognitions and mood, and alterations in arousal and reactivity. Additional criteria include the duration of symptoms [9]. Given that there are currently no laboratory biomarker tests for PTSD, this chapter will discuss the concept of using biomarkers to diagnose the potential for the existence

Biomarkers are defined as "cellular, biochemical, or molecular alterations that are measurable in biological media such as human tissues, cells, or fluids" [10-12]. Biomarkers can be meas‐ urable and quantifiable biological parameters, such as levels of protein or enzyme and hormone in the cerebrospinal fluid, saliva and blood, or mRNA specimen levels [10-12]. Those markers may be related to health and physiological conditions, metabolic processes, disease risk, psychiatric disorders, and environmental exposure, as well as disease diagnosis [13]. Biological changes, which link mechanism of drug action to clinical effectiveness, are also considered biomarkers [14]. Therefore, biomarkers may be considered as any substance, structure of molecule, or biological process that are measurable, influential and/or able to predict the incidence of outcome of disease (WHO International Program on Chemical Safety).

Biomarker research has advanced substantially as part of the Human Genome Project [15]. Initially, potential gene biomarkers were screened using high-throughput analytical instru‐ ments. Those markers were classified into four subgroups: type 0 biomarkers; type 1 biomark‐ ers; surrogate end point-type (type 2 biomarkers); and risk markers (http://en.wikipedia.org/ wiki/Human\_Genome\_Project). Depending on the function of those markers, they may be called imaging biomarkers (CT, PET, MRI), molecular biomarkers, or genetic markers. Molecular biomarkers include the markers in biological specimens (plasma, serum, saliva, cerebrospinal fluid, bronchoalveolar lavage, and biopsy). They can be peptides, proteins, lipids metabolites, enzymes, and other small molecules (http://en.wikipedia.org/wiki/ Human\_Genome\_Project). Genetic markers are micromRNA, mRNA and DNA mutations, or

of PTSD. Specific focus will be given to the potential of biomarker p11.

**3. Biomarker classification and application**

For the last 10 years, researchers have been focusing on developing a single test, such as a blood or genetic test, which may determine PTSD and simplify its treatment. In other medical fields, biomarkers have already been developed and used for diagnosis. For example, choles‐ terol measurements and genetic tests have been used for predicting the risks for heart attacks and Huntington's disease, respectively. In psychiatry, researchers hope to use the same strategies to identify and implement the biomarkers for predicting PTSD risk(s). However, the searching for such a test is still ongoing, though scientists are closer than ever to achieve this goal. Why is the search for biomarkers for PTSD needed when the disorder has been diagnosed by clinical-interview-based DSM diagnostic criteria for decades. Because, at least in part, biomarkers can help us better understand PTSD, its etiology and its pathologies, which in turn can lead to the development of more successful therapeutic approaches. It may help psychia‐ trists make faster and more effective decisions on the treatments based on the individual's pathology. In addition, biomarkers might identify high-risk populations that had not mani‐ fested any symptoms met in PTSD diagnostic criteria. To search for PTSD biomarkers, highthroughput omic approaches are required. The approaches used in biomarker studies of other diseases [16, 17] have just begun to be used in PTSD research. Although potential biomarker(s) for PTSD have been reported in the animal research [8] and human subjects research [6], the confirmation and validation of their clinical utility have not been accomplished. In PTSD biomarker studies, gene expression, metabolite levels and protein concentration in saliva [18], blood [19], cerebral spinal cord fluid [20], urine [21], and tissues [7] are compared between PTSD patients and healthy control subjects. In addition, physiological parameters (blood pressure [22], ECG [23], heartbeat [24], neurotransmitters [25-27], and brain imaging [28] are considered as biomarkers for PTSD.

PTSD biomarkers can be associated with PTSD-related behavioral characteristics (e.g., hypervigilance), the level or type of exposure to traumatic stress, genetic susceptibility, conditions of response to traumatic stress exposure, subclinical or clinical state, and conditions of response to therapy. During the course of PTSD, or after single or multiple traumatic stresses, the biomarkers can be identified. It also can be a predictor for PTSD-related risk, state, or pro‐ gression. Like biomarkers identified in cancer research, PTSD biomarker research may be used for antecedent, screening, diagnostic, monitoring stage, and prognosis. One biomarker may be associated with a single or multiple phenotypes of PTSD, while a single symptom can be associated with multiple PTSD biomarkers.

Few studies have evaluated the use of multiple biomarkers for patients' risk stratification [29]. The desirable properties of biomarkers for PTSD vary with their different usages. For example, a screening test requires having high sensitivity, specificity, predictive values, large likelihood ratios, and low cost to test a large population including normal and high-risk subjects. A diagnostic biomarker may be chosen for testing stages of the disease (acute and chronic). In those tests, sensitivity or specificity of monitoring biomarkers are less important because the marker from the same individual serves as his or her own control. The ability to monitor intraindividual variation is more important. Costs may be less important for prognostic markers since only those diagnosed with PTSD are subjects of focus.

In PTSD biomarker research, the sample size is often critical. A standard diagnostic biomarker test requires a relatively smaller sample size and a cross-sectional design. However, PTSD biomarker research requires a larger sample size and a prospective design. Although all biomarker features can be shown in one biomarker, a specific biomarker feature for use is the ultimate goal in the search for PTSD biomarkers. It would be ideal to have all the features to test PTSD and to help clinicians optimally manage PTSD patients with specific therapeutic targets. For example, the level of glucocorticoid [30] and/or concentration of epinephrine in the blood could be an indicator of responding to traumatic stress, or a plasma GABA level may evaluate whether or not the subject is recovering from trauma [31]. It is important that a biomarker test is an accurate, reproducible, standardized and acceptable procedure for PTSD diagnosis.

### **4.1. A strategy to identify a PTSD biomarker**

The development of PTSD biomarker(s) for clinical utility is a process from preclinical development (potential biomarker identification) to clinical validation (clinical utility appro‐ val) [8]. This long process includes three major steps: screening, analytical validation, and clinical validation. In the initial stage of screening, the high-throughput approaches are used to search for the potential biomarker(s). Analytical validation is laboratory or bench work, which involves sample selection, collection, storage, and determination of the optimum analytical procedure that provide high reproducibility and accuracy. Clinical validation (clinical utility) is the final step of the development of an accurate biomarker test, including testing sensitivity and specificity of the diagnosis [8].

#### **4.2. Screening biomarker(s) for PTSD**

Biomarker screening is the first step in identifying a potential PTSD biomarker. During the screening stage, researchers can start the study from animal models or human subjects. In general, animal models needs to be validated [29]. If human subjects are used, the bias should be avoided in the sample selection process. Since current animal models of PTSD have used different stress paradigms, a wide range of behavioral responses is obtained. In many prior studies, the data are presented by the mean values (with the standard deviation or the standard error) of the entire study group. It is known that only a proportion of individuals (20%–30%) who are exposed to a traumatic event will eventually develop PTSD [29]. Therefore, it is key to identify a marker for those subjects who are in the risk population to provide a solid basis for biomarker validation research [29].

Unlike the research in other medical fields, PTSD biomarker study provides little information about the molecular mechanisms of post-traumatic psychopathology. Previously, a genomewide screen in a validated animal model showed the possible biomarkers for PTSD [29]. A genomic analysis requires pure samples, which are identified by highly stringent criteria. The subjects are validated along three dimensions—analogous (similarity of phonotype), predic‐ tive (predictability of drug response or stress), and biological mechanism (regulation of gene expression and brain function). Once a potential biomarker is identified in the screening stage, an analytical validation is considered.

#### **4.3. Analytical validation of the PTSD biomarker assay**

ratios, and low cost to test a large population including normal and high-risk subjects. A diagnostic biomarker may be chosen for testing stages of the disease (acute and chronic). In those tests, sensitivity or specificity of monitoring biomarkers are less important because the marker from the same individual serves as his or her own control. The ability to monitor intraindividual variation is more important. Costs may be less important for prognostic markers

In PTSD biomarker research, the sample size is often critical. A standard diagnostic biomarker test requires a relatively smaller sample size and a cross-sectional design. However, PTSD biomarker research requires a larger sample size and a prospective design. Although all biomarker features can be shown in one biomarker, a specific biomarker feature for use is the ultimate goal in the search for PTSD biomarkers. It would be ideal to have all the features to test PTSD and to help clinicians optimally manage PTSD patients with specific therapeutic targets. For example, the level of glucocorticoid [30] and/or concentration of epinephrine in the blood could be an indicator of responding to traumatic stress, or a plasma GABA level may evaluate whether or not the subject is recovering from trauma [31]. It is important that a biomarker test is an accurate, reproducible, standardized and acceptable procedure for PTSD

The development of PTSD biomarker(s) for clinical utility is a process from preclinical development (potential biomarker identification) to clinical validation (clinical utility appro‐ val) [8]. This long process includes three major steps: screening, analytical validation, and clinical validation. In the initial stage of screening, the high-throughput approaches are used to search for the potential biomarker(s). Analytical validation is laboratory or bench work, which involves sample selection, collection, storage, and determination of the optimum analytical procedure that provide high reproducibility and accuracy. Clinical validation (clinical utility) is the final step of the development of an accurate biomarker test, including

Biomarker screening is the first step in identifying a potential PTSD biomarker. During the screening stage, researchers can start the study from animal models or human subjects. In general, animal models needs to be validated [29]. If human subjects are used, the bias should be avoided in the sample selection process. Since current animal models of PTSD have used different stress paradigms, a wide range of behavioral responses is obtained. In many prior studies, the data are presented by the mean values (with the standard deviation or the standard error) of the entire study group. It is known that only a proportion of individuals (20%–30%) who are exposed to a traumatic event will eventually develop PTSD [29]. Therefore, it is key to identify a marker for those subjects who are in the risk population to provide a solid basis

Unlike the research in other medical fields, PTSD biomarker study provides little information about the molecular mechanisms of post-traumatic psychopathology. Previously, a genomewide screen in a validated animal model showed the possible biomarkers for PTSD [29]. A

since only those diagnosed with PTSD are subjects of focus.

**4.1. A strategy to identify a PTSD biomarker**

testing sensitivity and specificity of the diagnosis [8].

**4.2. Screening biomarker(s) for PTSD**

for biomarker validation research [29].

diagnosis.

92 A Fresh Look at Anxiety Disorders

A standardized biomarker validation process used in oncology has been considered for use in PTSD biomarker research. Adaptation of this methodological approach includes a rigorous definition and evaluation of the whole process of PTSD biomarker determination (analytical validation), and an assessment of the impact of PTSD biomarker on clinical practices (clinical validation).

Here, we briefly discuss three of the several terms that relate to analytical validation of the biomarker assay for PTSD. The first term is **precision**, which relates to reproducibility in that others should obtain similar results when following the original protocol procedures [32, 33]. Precision includes repeatability, intermediate precision, and reproducibility. Repeatability indicates the levels of the precision under the same operating conditions over a short interval of time and is referred to as intra-assay precision. Intermediate precision is within laboratory variations (different days, analysts, equipment, etc.). The second term is **accuracy**, which relates to the closeness of agreement between the value that is accepted either as a conventional true value or an accepted reference value(http://www.fda.gov/downloads/Drugs/Guidance‐ ComplianceRegulatoryInformation/Guidances/ucm073381.pdf). The third term is **detection limit**, which refers to the lowest quantity of a substance relative to a blank value within a stated confidence limit (generally 1%) (http://en.wikipedia.org/wiki/Detection\_limit). A signal-tonoise ratio between 3:1 to 2:1 is generally acceptable for estimating the detection limit (http:// www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ ucm073381.pdf).

There are four major phases in the analytical validation stage, including setting up and standardizing operating procedures, and obtaining an internal quality control and external quality assessment. In phase one, operating procedures are established for PTSD biomarker determination. Phase two entails the validation of the operating procedures in terms of precision and accuracy according to the standards definition of operating procedures. Phase three obtains an internal quality control by evaluation of the validated standards within the laboratory. The final phase of the analytical validation is to conduct an external quality assessment comparison and assessment of their accuracy between laboratories.

In summary, analytical validation is to examine whether the procedure is suitable for testing PTSD. The analytical procedures in the protocol should be clearly defined. Thus, analytical validation should be done in different testing sites (Lab) using the same protocol. Validation includes the biomarkers' specificity, linearity, accuracy, precision (repeatability, intermediate precision, and reproducibility), range quantitation limit, and detection limit. Analytical validations must be completed prior to their use in clinical sites. In 1999, the United States Food and Drug Administration established final guidelines for the industry validation of analytical procedures and terminology (http://www.fda.gov/downloads/Drugs/GuidanceComplian‐ ceRegulatoryInformation/Guidances/ucm073381.pdf) [32, 33], which provides guidance on the validation of analytical procedures.

In the screening stage, high-throughput approaches, such as gene microarray and proteomics, are the important formats for simultaneous analyses of tens of thousands of molecules in a sample. These approaches require quality control and quality assurance. Many factors, including changes in the reaction conditions and calibration, influence the results in the analytical phase. Furthermore, since high-throughput approaches use many reagents or samples together in a single device, it makes the process more complex. Therefore, it is important to control analytical factors at different strategies by replicating analysis and normalization. The data with analytical validation for each operator and instrument can be provided to the next step, clinical validation.

#### **4.4. Clinical validation of the PTSD biomarker assay**

The development of a new PTSD biomarker test terminates with clinical validation that includes five phases: preclinical exploratory, clinical assay and validation, retrospective longitudinal, prospective screening, and PTSD control. Preclinical exploratory involves using a case-control approach to identify promising PTSD biomarker candidates. The second phase of clinical validation is to determine if a clinical biomarker assay can detect PTSD (populationbased). The third phase uses a nested case-control approach in a population cohort; retrospec‐ tive longitudinal study is conducted to verify if the biomarker is able to detect PTSD before it clinically manifests. In phase four, prospective screening is performed to determine the extent and characteristics of PTSD detected by tests in the subjects of cross-sectional cohort. Finally, if feasible, a randomized trial is conducted to examine the effect of test screening on reducing the burden of PTSD.

Clinical validation entails testing the ability of the markers to distinguish PTSD from non-PTSD cases, and to test the sensitivity and specificity. In this stage, it needs to find the truepositive rate (TPR), the proportion of PTSD cases who are biomarker-positive; the falsepositive rate (FPR), and the proportion of non-PTSD subjects who are biomarker-positive. Then, a receiver operating characteristic (ROC) curve should be plotted. In this plot, the TPR versus the FPR can be used as the discrimination threshold. During clinical validation, it is important to assess factors associated with the biomarker, including demographic details such as age, gender, and race.

Clinical validation of PTSD biomarkers should include both retrospective and prospective analyses. Using stored samples, a retrospective analysis can be used to determine the detective ability of the potential biomarker(s) and the cut-point. If it involves multiple potential PTSD biomarkers, those PTSD markers can be compared and developed to algorithms together. Longitudinal observation will examine the variability within-subjects and compare the timespecific ROC. Again, the cut-off for a biomarker is determined by a ROC curve.

Longitudinal observation provides data from the sequential testing point, which may add additional power to the PTSD biomarker. The key issue is how to obtain the appropriate and well-characterized samples from each collecting point. Sometimes the subjects cannot be identified again or have dropped out from the study. In addition, we found that PTSD biomarkers in the brain and in the blood are not necessarily altered in the same direction. Therefore, determining the relationship between biomarkers in the peripheral nervous system and central nervous system could be more important in the clinical validation study for PTSD, though sometimes those study designs are a challenge. Finally, clinical validity of PTSD biomarker test, including its rates of false negatives and false positives, should be well established before the tests enter clinical use. Meanwhile, bridging studies are required if changes of platform device occurred after clinical validation.

### **5. P11 as a potential PTSD biomarker**

procedures and terminology (http://www.fda.gov/downloads/Drugs/GuidanceComplian‐ ceRegulatoryInformation/Guidances/ucm073381.pdf) [32, 33], which provides guidance on

In the screening stage, high-throughput approaches, such as gene microarray and proteomics, are the important formats for simultaneous analyses of tens of thousands of molecules in a sample. These approaches require quality control and quality assurance. Many factors, including changes in the reaction conditions and calibration, influence the results in the analytical phase. Furthermore, since high-throughput approaches use many reagents or samples together in a single device, it makes the process more complex. Therefore, it is important to control analytical factors at different strategies by replicating analysis and normalization. The data with analytical validation for each operator and instrument can be

The development of a new PTSD biomarker test terminates with clinical validation that includes five phases: preclinical exploratory, clinical assay and validation, retrospective longitudinal, prospective screening, and PTSD control. Preclinical exploratory involves using a case-control approach to identify promising PTSD biomarker candidates. The second phase of clinical validation is to determine if a clinical biomarker assay can detect PTSD (populationbased). The third phase uses a nested case-control approach in a population cohort; retrospec‐ tive longitudinal study is conducted to verify if the biomarker is able to detect PTSD before it clinically manifests. In phase four, prospective screening is performed to determine the extent and characteristics of PTSD detected by tests in the subjects of cross-sectional cohort. Finally, if feasible, a randomized trial is conducted to examine the effect of test screening on reducing

Clinical validation entails testing the ability of the markers to distinguish PTSD from non-PTSD cases, and to test the sensitivity and specificity. In this stage, it needs to find the truepositive rate (TPR), the proportion of PTSD cases who are biomarker-positive; the falsepositive rate (FPR), and the proportion of non-PTSD subjects who are biomarker-positive. Then, a receiver operating characteristic (ROC) curve should be plotted. In this plot, the TPR versus the FPR can be used as the discrimination threshold. During clinical validation, it is important to assess factors associated with the biomarker, including demographic details such

Clinical validation of PTSD biomarkers should include both retrospective and prospective analyses. Using stored samples, a retrospective analysis can be used to determine the detective ability of the potential biomarker(s) and the cut-point. If it involves multiple potential PTSD biomarkers, those PTSD markers can be compared and developed to algorithms together. Longitudinal observation will examine the variability within-subjects and compare the time-

Longitudinal observation provides data from the sequential testing point, which may add additional power to the PTSD biomarker. The key issue is how to obtain the appropriate and

specific ROC. Again, the cut-off for a biomarker is determined by a ROC curve.

the validation of analytical procedures.

94 A Fresh Look at Anxiety Disorders

provided to the next step, clinical validation.

the burden of PTSD.

as age, gender, and race.

**4.4. Clinical validation of the PTSD biomarker assay**

Given that current diagnosis for PTSD rely on a clinician-administered interview, the devel‐ opment of a biomarker test for PTSD would be useful [7, 8]. There are no available laboratory blood biomarker tests for PTSD. We have pioneered the use of our patented blood p11 mRNA as a biomarker to differentiate PTSD from control and from other mental disorders. Our previous study demonstrates that p11 mRNA levels can be differentially detected in human blood from subjects with or without PTSD [7]. We, and others, found that p11 mRNA expres‐ sion is significantly changed in post-mortem cortex of patients with PTSD [7] and depression [34]. That suggests that p11 mRNA levels in the peripheral blood cells can serve as a biomarker for PTSD.

**P11**, annexin light chain [35], is a member of the S100 protein family. It is one of the proteins within the EF-hand super-family of Ca2+ binding proteins [36]. The p11 gene is located in chromosome 1q21 in humans and expressed in many types of cells and tissues, such as in the lungs, intestines, kidneys, brain, and blood of many species [37]. P11 protein was originally identified in a complex with the Ca2+/lipid-binding protein annexin A2 [36]. It regulated the function of exocytosis and endocytosis. Unlike other S100 proteins, it has crucial amino acid substitutions and deletions in the two EF-hand loops that render both Ca2+-binding sites inactive [36, 37]. It is locked in the equivalent of a Ca2+-loaded structure and in a permanently activated state. P11 binds to the target protein on hydrophobic cellular surfaces without Ca2+. Thus, p11 regulates the function of several membrane proteins, such as annexin II and the 5- HT1B receptor, which are associated with mental disorders [34]. In the nucleus, p11 participates in the regulation of the stress response. P11 is up-regulated by stress or stress hormones in the brain [7]. Stress-induced p11 overexpression is mediated by the glucocorticoid receptor (GR), which interacts with glucocorticoid receptor response elements (GREs) in the p11 promoter region [7]. These observations have received support from our data showing that mRNA levels of p11 increased in the post-mortem prefrontal cortex (area 46) of PTSD patients. Furthermore, in rats we showed that three days of inescapable shock induced over expression of p11 mRNA in the prefrontal cortex (PFC) and elevated corticosterone levels in the plasma [7]. This upregulation of p11 expression can be countered by either a glucocorticoid receptor antagonist, RU486, or by mutating two of the three GREs (GRE2 and GRE3) [7]. Our preliminary data (Fig. 1, unpublished data) also demonstrated that p11 was significantly over-expressed in the blood of soldiers with PTSD who were deployed, compared to deployed soldiers who did not have PTSD (Fig. 1a and 1b). Such overexpression is significantly associated with the severity of PTSD symptoms (Fig. 1c). Our results warrant further exploration of p11 as a potential biomarker for PTSD in a large sample size.

**Figure 1.** P11 mRNA and protein levels were significantly higher in subjects with PTSD (n=67) than that in the non-PTSD controls (n=67), and the relationship between blood p11 levels and PTSD symptom severity (unpublished data). (a) P11 mRNA level was significantly higher in subjects with PTSD than that in the non-PTSD controls (\*\*p<0.01). (b) P11 protein level was significantly higher in subjects with PTSD than that in the non-PTSD controls (\*\*\*p<0.001). (c) The relationship between blood p11 protein levels and PTSD checklist (PCL) score (p<0.0027).

### **6. Biorepository or biobank in biomarker study**

To obtain a large quantity of good quality samples is a challenge. It requires developing a standardized protocol for sample collection, storage, and quantitative control. A biobank will provide such opportunity. A preliminary type of biobank, a biorepository can store biological samples (usually human) for use in PTSD biomarker research. The biobank market is expand‐ ing with a significant increase in using human tissues, blood, and other biomaterials to do biomarker research, and pharmaceutical and diagnostic tool development [38]. In 2008, there were 270 million specimens in biobanks. Each year, about 20 million samples have been collected for research, including biomarker studies [39], indicating worldwide changes in the nature of biomedical research. In general, more and more biobanks have been established. They are established by multiple research centers, leading to an infrastructure of nextgeneration research demand [40]. A typical example is the Psychiatric Genomics Consortium (PGC) that is comprised of more than 80 institutions. The PGC has samples from more than 150,000 people; of which, 36,989 samples are from subjects with diagnosed schizophrenia [41]. Recently, using the PGC samples, researchers have spotted 108 genetic loci in the DNA sequence of schizophrenia. The large PGC sample has also allowed for the development of an algorithm to calculate a 'risk score' for each variant's contribution to schizophrenia. PGC plans to sequence 100,000 subject samples with mental illnesses in an effort to identify the meaningful biomarker associations [41].

However, there are many issues for biobanks ahead, including ethical, legal, and social issues pertaining to their existence, the fairness of collecting donations from vulnerable populations, providing informed consent to donors, the logistics of data disclosure to participants, the right to ownership of intellectual property, and the privacy and security of donors who participate [39]. Nevertheless, biobanks will provide a great opportunity to researchers in the PTSD biomarker study.

### **7. Our biorepository and biomarker study, including p11 research**

Since 2009, we have collected blood and saliva samples from soldiers who were deployed to Iraq and Afghanistan. To date, over 2,000 blood and 5,000 saliva samples have been collected. This study was initiated at Fort Bragg in 2009 and expanded to multiple Army National Guard units throughout California, Pennsylvania, and Guam in 2011. Biological samples and detailed mental health data, using DSM driven surveys, were voluntarily collected from soldiers, including ~500 before, during, and following a deployment to Iraq or Afghanistan, to allow for a longitudinal assessment. The mental health surveys contained established self-report inventories (e.g., PCL, GAD, and PHQ). Using our biorepository dataset to examine p11 as a potential PTSD biomarker may help scientists discover why some people, particularly those in the military, develop PTSD, depression, and suicidal behaviors while others do not.

### **Author details**

PTSD (Fig. 1a and 1b). Such overexpression is significantly associated with the severity of PTSD symptoms (Fig. 1c). Our results warrant further exploration of p11 as a potential biomarker

**Figure 1.** P11 mRNA and protein levels were significantly higher in subjects with PTSD (n=67) than that in the non-PTSD controls (n=67), and the relationship between blood p11 levels and PTSD symptom severity (unpublished data). (a) P11 mRNA level was significantly higher in subjects with PTSD than that in the non-PTSD controls (\*\*p<0.01). (b) P11 protein level was significantly higher in subjects with PTSD than that in the non-PTSD controls (\*\*\*p<0.001). (c)

To obtain a large quantity of good quality samples is a challenge. It requires developing a standardized protocol for sample collection, storage, and quantitative control. A biobank will provide such opportunity. A preliminary type of biobank, a biorepository can store biological samples (usually human) for use in PTSD biomarker research. The biobank market is expand‐ ing with a significant increase in using human tissues, blood, and other biomaterials to do biomarker research, and pharmaceutical and diagnostic tool development [38]. In 2008, there were 270 million specimens in biobanks. Each year, about 20 million samples have been collected for research, including biomarker studies [39], indicating worldwide changes in the nature of biomedical research. In general, more and more biobanks have been established.

The relationship between blood p11 protein levels and PTSD checklist (PCL) score (p<0.0027).

**6. Biorepository or biobank in biomarker study**

for PTSD in a large sample size.

96 A Fresh Look at Anxiety Disorders

Lei Zhang1\*, Xian-Zhang Hu1 , He Li1 , Xiaoxia Li1 , Stanley Smerin1 , Dale W. Russell1 , Angela Boutte2 , Berwin Yuan1 , Nora Wang1 , Ze Chen1 and Robert J. Ursano1

\*Address all correspondence to: Lezhang@usuhs.edu

1 Uniformed Services University of the Health Sciences, Department of Psychiatry, Bethesda, MD, USA

2 Brain Trauma, Neuroprotection, and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA

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100 A Fresh Look at Anxiety Disorders

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Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60594

#### **Abstract**

A universal phenomenon equally ancient as the history of mankind, suicide is defined as the willful and intentional ending of one's own life. Risk factors for suicidal behav‐ ior are traumatic childhood and adulthood experiences, negative interfamily interac‐ tions, social isolation, decreased social solidarity, financial troubles, losses, despair, impulsivity, and migration. Recognized as a critical public health problem, prelimina‐ ry causes of suicide are financial, religious, political, social, cultural, and medical in addition to mental disorders like depression and alcohol addiction. It has been proven in a number of researches till today that there is a correlation between major depres‐ sion, bipolar disorder, schizophrenia, borderline personality disorder, alcohol-drug use, and suicidal behavior. Nonetheless, the relation between anxiety disorders and suicidal behavior has not been clearly defined to date. The evidences gathered so far reveal that panic disorder is only an independent risk factor for suicide attempt. The limited number of studies on this domain provided nonhomogenous results. It is however a point to keep in mind that if anxiety disorders are codiagnosed with men‐ tal disorders, they pose risk for suicidal behavior. In different studies with a wider sampling in this domain, analyzing the effect of specific anxiety disorders on suicidal behavior might be useful for suicide prevention programs.

**Keywords:** Anxiety disorders, suicidal thoughts, suicide attempts, comorbid psychiat‐ ric disorders, suicidal behavior

### **1. Introduction**

Nowadays, suicide is a major public health issue worldwide. Suicide is undoubtedly the most tragic event in human life. Globally speaking, around one million people commit suicide each year. Suicide is possibly witnessed among a wide range of population extending from normal individuals reacting differently to stress-triggering life conditions to people diagnosed with a mental disorder. Mental disorders as suicide causes have been studied in numerous researches

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and the correlation between depression and suicide has been particularly emphasized because major depression disorder comes first among the mental disorders that are related to both completed suicide and also suicidal ideation and attempt. The relation between anxiety disorders and suicidal behavior has been examined in limited numbers of studies with differing results. Some studies posited that there might be a relation between anxiety disorder and suicidal behavior, while in other studies it was posited that anxiety disorders on their own cannot be effective in triggering suicidal behavior. Anxiety disorders often cooccur with depression, and this may be masking a risk of suicidal behavior specifically related to anxiety. This higher likelihood was seen despite controlling for current depression, highlighting the importance of clinicians considering suicidal risk when working with anxiety patients who do not necessarily also have a diagnosis of depression. Although anxiety has been proposed to be a potentially modifiable risk factor for suicide, research examining the relationship between anxiety and suicidal behaviors has demonstrated mixed results. Until recently, anxiety disorders were not regarded as an independent risk factor for suicidal behavior which in turn limited the number of studies focusing on the significant relation between anxiety disorder and suicidal behavior. In a different saying, suicidal ideation in anxiety-diagnosed patients went unnoticed. Strong evidences have been gathered proving that panic disorder is an independent risk factor for suicide. There are uncertain findings about the possibility that specific anxiety disorders such as generalized anxiety disorder, obsessive-compulsive disor‐ der, and posttrauma stress disorder may be independent risk factors for suicide. There are, however, stronger evidences that when anxiety disorder is codiagnosed with comorbid depression, bipolar disorder, schizophrenia, drug use, and personality disorders the risk may be substantially higher. In other words, controversy exists whether anxiety disorders are independently associated (i.e., after adjusting for comorbid mental disorders) with suicidal ideation and suicide attempts. Despite the existence of literature studies providing nonho‐ mogenous findings, it is of great importance that clinicians focus more eagerly and attentively on suicide behavior in patients with anxiety disorder – particularly in patients codiagnosed with mental-disorder – to provide assistance to suicide prevention attempts. In this chapter, the relation between suicidal behavior and the anxiety disorder will be discussed.

### **2. Anxiety disorders**

Anxiety disorders belong to the most frequent mental disorders and are often characterized by an early onset and a progressive, persistent/chronic, or recurrent course. Several individual, familial, and environmental risk factors for adverse course characteristics of anxiety disorders (including higher persistence, lower probability of remission, and increased risk of recurrence) have been identified, and previous research suggests that clinical features of anxiety (e.g., higher severity, duration, and avoidance) as well as comorbid other mental disorders are particularly useful for predicting an unfavorable course of anxiety disorders [1]. The literature reviewed here is consistent in showing that anxiety disorders are common psychiatric disorders that typically has an early age of onset, a chronic course, and a high degree of comorbidity with mood disorders and other psychiatric disorders [2]. Anxiety disorders are one of the most prevalent of all psychiatric disorders in the general population [3-5]. Phobias are the most common with the highest rates for simple phobia (SP) and agoraphobia. For example, SP is the most common anxiety disorder, with up to 49% of people reporting an unreasonably strong fear. Among general population, prevalence of social anxiety disorder (SAD) meeting DSM-IV diagnosis criteria is circa 13%. Among general population, prevalence of posttraumatic stress disorder (PTSD) is 7.8%; however among particular groups (war veterans with 20%, domestic violence victim women 12%), higher prevalence of PTSD has been reported [6]. Panic disorder (PD) and obsessive-compulsive disorder (OCD) are less frequent, and there are discordant results for SAD and generalized anxiety disorder [7]. The epidemio‐ logical studies have shown that anxiety disorders are highly prevalent and important causes of functional impairment [2, 8]. However, due to their methodic differences, epidemiologic studies fail to adequately explain the effects of anxiety disorders on functionality since the high frequency of confusing sociodemographic variables (gender, age, race, ethnic structure, education, and marital status) can play different roles in the symptom severity and course of anxiety disorders [7]. Agoraphobia, SP, and generalized anxiety disorder (GAD) are more common in female, while there is no gender difference for SAD, PD, and OCD [6]. Anxiety disorders are more common among separated, divorced, or widowed people between ages 25 and 44. Anxiety disorders are rare among age 65 and above. Start age for anxiety disorders however varies for specific anxiety disorders. For instance, phobic disorders start at early age, while panic disorder is witnessed during early adulthood stage. Rather than epidemiological studies, stressful life events, childhood experiences, and familial factors as risk factors have been examined in clinical researches. Anxiety disorders are usually chronic and persistent and are generally accompanied with other psychiatric disorders such as other anxiety disorders, depressive disorders, personality disorders, and drug use. These codiagnosed conditions may negatively affect functionality and life quality. Further study is needed to better understand the comorbidity between anxiety disorders, the consistently higher rates of anxiety disorders, and the differential effects of socioeconomic and cultural factors on anxiety disorders.

### **3. Suicidal behaviors**

and the correlation between depression and suicide has been particularly emphasized because major depression disorder comes first among the mental disorders that are related to both completed suicide and also suicidal ideation and attempt. The relation between anxiety disorders and suicidal behavior has been examined in limited numbers of studies with differing results. Some studies posited that there might be a relation between anxiety disorder and suicidal behavior, while in other studies it was posited that anxiety disorders on their own cannot be effective in triggering suicidal behavior. Anxiety disorders often cooccur with depression, and this may be masking a risk of suicidal behavior specifically related to anxiety. This higher likelihood was seen despite controlling for current depression, highlighting the importance of clinicians considering suicidal risk when working with anxiety patients who do not necessarily also have a diagnosis of depression. Although anxiety has been proposed to be a potentially modifiable risk factor for suicide, research examining the relationship between anxiety and suicidal behaviors has demonstrated mixed results. Until recently, anxiety disorders were not regarded as an independent risk factor for suicidal behavior which in turn limited the number of studies focusing on the significant relation between anxiety disorder and suicidal behavior. In a different saying, suicidal ideation in anxiety-diagnosed patients went unnoticed. Strong evidences have been gathered proving that panic disorder is an independent risk factor for suicide. There are uncertain findings about the possibility that specific anxiety disorders such as generalized anxiety disorder, obsessive-compulsive disor‐ der, and posttrauma stress disorder may be independent risk factors for suicide. There are, however, stronger evidences that when anxiety disorder is codiagnosed with comorbid depression, bipolar disorder, schizophrenia, drug use, and personality disorders the risk may be substantially higher. In other words, controversy exists whether anxiety disorders are independently associated (i.e., after adjusting for comorbid mental disorders) with suicidal ideation and suicide attempts. Despite the existence of literature studies providing nonho‐ mogenous findings, it is of great importance that clinicians focus more eagerly and attentively on suicide behavior in patients with anxiety disorder – particularly in patients codiagnosed with mental-disorder – to provide assistance to suicide prevention attempts. In this chapter,

the relation between suicidal behavior and the anxiety disorder will be discussed.

Anxiety disorders belong to the most frequent mental disorders and are often characterized by an early onset and a progressive, persistent/chronic, or recurrent course. Several individual, familial, and environmental risk factors for adverse course characteristics of anxiety disorders (including higher persistence, lower probability of remission, and increased risk of recurrence) have been identified, and previous research suggests that clinical features of anxiety (e.g., higher severity, duration, and avoidance) as well as comorbid other mental disorders are particularly useful for predicting an unfavorable course of anxiety disorders [1]. The literature reviewed here is consistent in showing that anxiety disorders are common psychiatric disorders that typically has an early age of onset, a chronic course, and a high degree of comorbidity with mood disorders and other psychiatric disorders [2]. Anxiety disorders are

**2. Anxiety disorders**

102 A Fresh Look at Anxiety Disorders

The currently accepted nomenclature of suicide-related behaviors identifies suicide, nonfatal suicide attempts, and suicidal ideation [9]. Suicidal ideation is verbally expressing one's ideas about killing himself/herself. Suicide attempt is performing behaviors with the intention of killing oneself not ending with death but potentially causing major injuries. Completed suicide is dying as a result of the behavior performed to kill oneself. It is a requirement to make such classification for suicidal behaviors since for three different groups risk factors and clinical presentations vary. Hence this classification is needed in the prevention of suicides likewise. Global estimates suggest that each year there are 10–20 million suicide attempts and one million completed suicides [10]. Suicide attempts are costly in terms of occupational and interpersonal disruption [11]. Moreover, substantial financial costs are associated with the intensive psychiatric resources devoted to these patients [12]. Suicide is a multivariate phenomenon occurring with the combined effect of a multitude of factors such as psycholog‐ ical, sociological, economical, and cultural. That explains the reason why suicide can be witnessed among a vast sampling group ranging from normal individuals to patients with severe mental disorders. Mood disorders and personality disorders (borderline personality disorder in particular) are psychiatric problems most frequently associated with suicide. Besides, there have been striking findings recently that point to the increasing effect of anxiety disorders on suicide. On that account this relation should definitely be analyzed in the prevention of suicide, which is a crucial public health problem. In cases with anxiety disorder, analyzing suicidal ideation and suicide attempt may prevent completed suicides hence lower the ratios of completed suicide; because suicidal ideation and preattempted suicide are the biggest risk factors for a completed suicide [10, 13, 14]. Studying such thoughts and behaviors, therefore, may increase our understanding of who is likely to attempt or complete suicide, potentially informing suicide risk management and prevention efforts. Psychiatric disorders are one the primary risk factors for suicidality, with up to 95% of suicides committed by individuals with one or more disorders.

#### **4. Anxiety disorders and suicidal behaviors**

Patients with anxiety disorders are at high risk for suicidal ideation, regardless of whether the suicidal ideation is due to anxiety disorders itself or to cooccurring conditions. In evaluating the literature, it is necessary to review general requirements for establishing anxiety as a risk factor for suicidal behaviors [9]. In addition to establishing a meaningful and consistent interrelation of anxiety with suicidal behavior, the other requirement is the absence of a third variance (mixing factor) between suicidal behaviors and anxiety. Besides, anxiety must have existed before suicidal behavior and in suicidal behaviors anxiety must act as the independent risk factor. Psychiatric disorders are one of the primary risk factors for suicidality, with up to 95% of suicides committed by individuals with one or more disorder [15]. In particular, the mood and anxiety disorders are associated with suicide ideation and attempts [16-19]. The relationship between anxiety disorders and suicide-related behaviors has received a modest amount of attention. However, research has also accumulated over the past several years indicating that anxiety disorders confer unique risk of suicide [20, 21]. The presence of current or lifetime anxiety disorders, including panic disorder, social phobia, generalized anxiety disorder, and posttraumatic stress disorder, are associated with increased suicide risk [10, 18, 22, 23]. Individuals with anxiety disorders demonstrate increased suicidal ideation and rates of self injury and more frequent suicide attempts than those without mental health disorders [10, 16, 17]. For this reason, it is of vital importance to comprehend and manage the risk factors for suicide among individuals with anxiety disorders. Despite the prevalence of high risk for suicide within cases with anxiety disorder, the determinants of suicide risk in this group have not yet been clearly established. In other words, anxiety disorders are very common and increase risk for suicide attempts. Little is known about predictors of increased risk specifically among individuals with anxiety disorders [19]. Studies of individuals with specific anxiety disorders including panic disorder, social phobia, and posttraumatic stress disorder indicate that the additional presence of depression and substance use disorders increases suicide risk

[10, 24]. Severity and aspects of functional impairment are also related to suicide risk in patients with anxiety disorders. For example, anxiety symptom severity is associated with increased suicidal ideation and attempts in patients with PD and patients with PTSD [10, 25, 26]. Associations between suicide risk and impairment in general functioning in PTSD and social functioning in both PTSD and PD are also documented [27, 28]. Twelve-month prevalence rates of suicidal ideation in patients with obsessive-compulsive disorder (OCD, 27.3%), the prevalence rate of suicide attempts in panic disorder (3.6%) and the prevalence rate of suicide attempts in OCD (3.3%) were the highest [21]. The overall 12-month and lifetime prevalence of GAD was 0.8% and 1.2%, respectively. Being older than 25 years and female, lower education level, unemployed status, and lower monthly income were associated with increased risk of GAD in China [29]. It remains unclear whether certain anxiety disorders are risk factors for suicide. For instance, Uebelacker et al. [19] have reported that PTSD, major depressive disorder (MDD), intermittent depressive disorder, epilepsy, pain and low social functionality are, according to univariate analysis, predictors of suicide attempt. In the same study, the findings of multivariate analysis showed that, even when the suicide attempts of the past are controlled, MDD and intermittent depressive disorder are independent risk factors in current attempts for suicide. However, it was concluded in this research that except panic disorder, no other specific anxiety disorder constituted an independent risk factor for suicide attempt. Mood disorders and past history of suicide attempts are the most powerful predictors of a future suicide attempt. Particularly, the patients with comorbid major depressive disorder anxiety are at higher risk for suicide. Thereby primary care health service doctors, emergency and mental health professionals, and clinicians who frequently come across with anxiety disor‐ dered cases should be alerted and attentive against potential suicidal ideation and suicide attempts among these patients.

#### **4.1. Anxiety disorders and completed suicide: Associated factors**

ical, sociological, economical, and cultural. That explains the reason why suicide can be witnessed among a vast sampling group ranging from normal individuals to patients with severe mental disorders. Mood disorders and personality disorders (borderline personality disorder in particular) are psychiatric problems most frequently associated with suicide. Besides, there have been striking findings recently that point to the increasing effect of anxiety disorders on suicide. On that account this relation should definitely be analyzed in the prevention of suicide, which is a crucial public health problem. In cases with anxiety disorder, analyzing suicidal ideation and suicide attempt may prevent completed suicides hence lower the ratios of completed suicide; because suicidal ideation and preattempted suicide are the biggest risk factors for a completed suicide [10, 13, 14]. Studying such thoughts and behaviors, therefore, may increase our understanding of who is likely to attempt or complete suicide, potentially informing suicide risk management and prevention efforts. Psychiatric disorders are one the primary risk factors for suicidality, with up to 95% of suicides committed by

Patients with anxiety disorders are at high risk for suicidal ideation, regardless of whether the suicidal ideation is due to anxiety disorders itself or to cooccurring conditions. In evaluating the literature, it is necessary to review general requirements for establishing anxiety as a risk factor for suicidal behaviors [9]. In addition to establishing a meaningful and consistent interrelation of anxiety with suicidal behavior, the other requirement is the absence of a third variance (mixing factor) between suicidal behaviors and anxiety. Besides, anxiety must have existed before suicidal behavior and in suicidal behaviors anxiety must act as the independent risk factor. Psychiatric disorders are one of the primary risk factors for suicidality, with up to 95% of suicides committed by individuals with one or more disorder [15]. In particular, the mood and anxiety disorders are associated with suicide ideation and attempts [16-19]. The relationship between anxiety disorders and suicide-related behaviors has received a modest amount of attention. However, research has also accumulated over the past several years indicating that anxiety disorders confer unique risk of suicide [20, 21]. The presence of current or lifetime anxiety disorders, including panic disorder, social phobia, generalized anxiety disorder, and posttraumatic stress disorder, are associated with increased suicide risk [10, 18, 22, 23]. Individuals with anxiety disorders demonstrate increased suicidal ideation and rates of self injury and more frequent suicide attempts than those without mental health disorders [10, 16, 17]. For this reason, it is of vital importance to comprehend and manage the risk factors for suicide among individuals with anxiety disorders. Despite the prevalence of high risk for suicide within cases with anxiety disorder, the determinants of suicide risk in this group have not yet been clearly established. In other words, anxiety disorders are very common and increase risk for suicide attempts. Little is known about predictors of increased risk specifically among individuals with anxiety disorders [19]. Studies of individuals with specific anxiety disorders including panic disorder, social phobia, and posttraumatic stress disorder indicate that the additional presence of depression and substance use disorders increases suicide risk

individuals with one or more disorders.

104 A Fresh Look at Anxiety Disorders

**4. Anxiety disorders and suicidal behaviors**

The presence of anxiety disorder is frequently associated with suicide ideation and behaviors. Considering the high costs of suicidal behaviors for the individuals and also the society, it is a foremost priority to prevent suicide. Grasping the factors related to increased risk for suicide among people with anxiety disorders may be contributive to suicide prevention attempts [10]. Anxiety disorders are independent risk factors for suicide attempts and underscore the importance of anxiety disorders as a serious public health problem [17]. The relationship between anxiety disorders and completed suicide is not known exactly. There are a limited number of studies on this subject [30, 31]. It is unclear whether clinical and behavioral suicide risk factors, identified primarily among men, can be extended to women. Personality variants and gender differences among suicide completers with psychopathological autopsy method were investigated. Among women, the ratio of completed suicides is lower than men. Impul‐ sivity and alcohol use are risk factors for completed suicides. It is less common among women to see lifelong alcohol consumption, and among women with alcohol addiction, there is less prevalence of comorbid depression when compared to men. There exists a correlation between alcohol consumption and impulsivity. The low ratio of impulsivity among women triggers alcohol consumption as well. Furthermore, when the relation between impulsivity and applied suicide method is examined, it surfaces that among cases with high ratio of impulsivity, the tendency to apply violence methods is more common. It is argued that women prefer non‐ violent suicide methods less pain causing but regardless of their sex, cases with anxiety disorder apply to nonviolent methods more frequently. On the other hand, when high ratio of impulsivity is combined with alcohol consumption, there may occur an elevated risk of suicide for both sexes [30].

#### **4.2. Anxiety disorders and attempted suicide: Associated factors**

The relationship between anxiety disorders and racial and ethnic differences has been studied in several research. For instance, Vanderwerker et al. [32] examined in their study covering 131 adults from different ethnic and racial origins (more than half of the cases with African American roots) the differences of risk factors for suicidal ideation and suicide attempts. They have detected that among young white adults, anxiety disorder (not depression) has an independent relation with suicide tendency, while there is no such relationship for African-Americans among whom there is a significant relation between suicidal behavior and social support could be identified. These findings clearly prove that suicide risk factors vary among races and ethnicities [32]. The results suggest that race/ethnicity-specific risk profiles may improve the detection of suicidality in vulnerable populations. But, Beautrais et al. [33] were found no ethnic differences in suicidal ideation. Risks of suicidal ideation, plan, and attempt were associated with mood disorder, substance use disorder, and anxiety disorder. Major depression was the specific disorder most strongly associated with suicidal ideation, plan, and attempt [33]. In a different study based on society sampling, a number of variables (demo‐ graphic, work status, mental and physical health condition, personality features, stressful life experiences, and social environment) impacting the suicide-attempt speed in cases with suicidal ideation have been examined. Among age groups between 20–24 and 40–44 having committed suicide attempt, it has been seen that there was a higher ratio of suicidal ideation with respect to age-matched groups and higher levels of anxiety and depression. Upon checking the remaining variables, it has been reported that in cases between ages 20–24, rather than suicidal ideation but anxiety itself constituted a risk factor for suicide attempt. Particularly among men between ages 40–44, physical diseases and unemployment, rather than anxiety and depression, posed greater risks for suicide attempt. In a different saying, Fairweather et al. [34] found that ideators and attempters experience comparable levels of depression and anxiety. Rates of self-harm and associations between self-harm and suicidal behaviors, anxiety, hostility, and paranoid ideas were reported by Fliege et al. [35]. Although there has been significant interest in whether anxiety disorders are risk factors for suicidal behavior, this remains a controversial area. Cross-sectional community and clinical studies have repeatedly demonstrated in univariate models that anxiety disorders are associated with suicidal ideation, attempted suicide, and completed suicides. In multivariate models, it has been questioned whether panic disorder is associated with suicidal behavior after adjusting for other anxiety and psychiatric disorders. Because anxiety disorders are highly comorbid with other anxiety disorders and tend to cluster together, it is important to address whether anxiety disorders as a group of psychiatric disorders have an impact on suicidal behavior after adjusting for other types of other psychiatric disorders (especially mood and substance use disorders) [16].

### **5. Specific anxiety disorders and suicidal behaviors**

The relationship between anxiety disorders and suicidal behaviors has not received sufficient amount of interest till present age. Literature review shows that when there is a definite result for a single anxiety disorder, anxiety disorders in general have high frequency relation with suicidal ideation; however its relationship with suicide attempt is not definite [9, 18, 36]. General tendency indicates that for each anxiety disorder there is a similar risk for suicide primarily obsessive-compulsive disorder, generalized anxiety disorder, and social anxiety disorder are associated with suicide ideation. The only specific anxiety disorder related most with suicide attempt is panic disorder [37]. In addition, a clear relationship was reported between PTSD and suicidal thoughts and behaviors, irrespective of the type of trauma experienced. It has been suggested that PTSD has a strong association with suicidality, predicting subsequent suicidal attempts [28, 38].

### **5.1. Panic disorder and suicide**

tendency to apply violence methods is more common. It is argued that women prefer non‐ violent suicide methods less pain causing but regardless of their sex, cases with anxiety disorder apply to nonviolent methods more frequently. On the other hand, when high ratio of impulsivity is combined with alcohol consumption, there may occur an elevated risk of suicide

The relationship between anxiety disorders and racial and ethnic differences has been studied in several research. For instance, Vanderwerker et al. [32] examined in their study covering 131 adults from different ethnic and racial origins (more than half of the cases with African American roots) the differences of risk factors for suicidal ideation and suicide attempts. They have detected that among young white adults, anxiety disorder (not depression) has an independent relation with suicide tendency, while there is no such relationship for African-Americans among whom there is a significant relation between suicidal behavior and social support could be identified. These findings clearly prove that suicide risk factors vary among races and ethnicities [32]. The results suggest that race/ethnicity-specific risk profiles may improve the detection of suicidality in vulnerable populations. But, Beautrais et al. [33] were found no ethnic differences in suicidal ideation. Risks of suicidal ideation, plan, and attempt were associated with mood disorder, substance use disorder, and anxiety disorder. Major depression was the specific disorder most strongly associated with suicidal ideation, plan, and attempt [33]. In a different study based on society sampling, a number of variables (demo‐ graphic, work status, mental and physical health condition, personality features, stressful life experiences, and social environment) impacting the suicide-attempt speed in cases with suicidal ideation have been examined. Among age groups between 20–24 and 40–44 having committed suicide attempt, it has been seen that there was a higher ratio of suicidal ideation with respect to age-matched groups and higher levels of anxiety and depression. Upon checking the remaining variables, it has been reported that in cases between ages 20–24, rather than suicidal ideation but anxiety itself constituted a risk factor for suicide attempt. Particularly among men between ages 40–44, physical diseases and unemployment, rather than anxiety and depression, posed greater risks for suicide attempt. In a different saying, Fairweather et al. [34] found that ideators and attempters experience comparable levels of depression and anxiety. Rates of self-harm and associations between self-harm and suicidal behaviors, anxiety, hostility, and paranoid ideas were reported by Fliege et al. [35]. Although there has been significant interest in whether anxiety disorders are risk factors for suicidal behavior, this remains a controversial area. Cross-sectional community and clinical studies have repeatedly demonstrated in univariate models that anxiety disorders are associated with suicidal ideation, attempted suicide, and completed suicides. In multivariate models, it has been questioned whether panic disorder is associated with suicidal behavior after adjusting for other anxiety and psychiatric disorders. Because anxiety disorders are highly comorbid with other anxiety disorders and tend to cluster together, it is important to address whether anxiety disorders as a group of psychiatric disorders have an impact on suicidal behavior after adjusting for other types of other psychiatric disorders (especially mood and substance use disorders) [16].

**4.2. Anxiety disorders and attempted suicide: Associated factors**

for both sexes [30].

106 A Fresh Look at Anxiety Disorders

Suicidal behaviors are multifactorial behaviors. While, historically, anxiety has been regarded as an important risk factor in suicidal behaviors, epidemiological studies carried out on general population or panic patients have evidenced the possible links between suicidal behaviors and the occurrence of panic attacks [39, 40]. Both panic attacks and panic disorders are, in the society and primary health care service, independently related with the increased suicide attempt risk. In epidemiologic samplings, panic disorder is, like major depressive disorder, a risk factor for lifelong suicide ideation and suicide attempt [40-42]. For example, an association between panic and suicidal ideation has been reported by Goodwin and Roy-Byrne [43]. Epidemiologic catchment area (ECA) studies indicate that, when contrasted with other psychiatric disorders, panic disorder is associated with increased suicide ideation and suicide attempt risk [40]. Additionally, epidemiologic data show that when panic disorder is codiagnosed with major depression, alcohol addiction, personality disorders, and cocaine use, there is higher risk for suicide attempt [44, 45]. For instance, Goodwin and Roy-Byrne report that despite the vital role comorbid depression and drug abuse play, attempts for the last one year (not lifelong) are independently related to panic disorder [43]. It has been suggested that panic disorder may not increase past suicide attempt systematically but may climb the suicide attempt in the future. In a vast majority of the monitoring studies of patients with anxiety disorder, there was 20% ratio of suicide caused deaths like the results in major depressive disorder. Similarly, the ratios in suicide attempts have been similar to major depressive disorder and panic disorder [40, 46]. Existing findings are quite remarkable. Patients who suffered from major depressive disorder with related panic disorder were given to more impulsive suicide attempts, even if the difference with depressed patients without panic disorder was statistically insignificant [39]. Primary care patients with PD are at high risk for suicidal ideation, and patients with PD and cooccurring MDD are at especially high risk. Patients with PD in primary care thus should be assessed routinely for suicidal ideation and depression [42]. Although in society-based studies it is indicated that there is a strong relation between PD and suicide ideation, in many other studies with clinic sampling (receiving psychiatric treatment and hospitalized in psychiatry clinic or hospital), no statistically significant relation between PD and suicidal ideation could be detected [24, 47]. For example, Warshaw et al. [24] reported that there was no association between PD and suicidal ideation after controlling for common comorbid psychiatric disorders. In another study, it was revealed that suicidal behavior risk in panic disorder is not higher than the risk in major depressive disorder [42]. Dammen et al. [47] could not find any difference in terms of suicidal ideation between patients with or without panic disorder. Several mental disorders, such as personality disorders, and life events that that have been associated with suicidality, e.g., early childhood abuse, were not assessed and may account partially for the observed association between PD and suicidal ideation [48, 49]. In some clinical studies, patients with PD and borderline personality disorder were at signifi‐ cantly higher risk of suicidal behavior than were PD patients with panic disorder alone [24]. To sum up, there is still an ongoing discussion about the relation between panic disorder and suicide behavior. It is not yet identified if panic disorder singly or when comorbid with other mental disorders like major depressive disorder is effective in suicidal behavior [24, 40, 50]. Thus, the data indicate that the risk of suicide in panic disorder is substantial. As a consequence, clinicians should alert themselves to this preventable outcome and approach treatment with added caution.

#### **5.2. Posttraumatic stress disorder and suicide**

Posttraumatic stress disorder (PTSD) is frequently associated with suicidal ideation and suicide attempts. Suicide is an important cause of death in veterans, and the risk for intentional death continues to be high many years after service [51]. Suicidal behavior is a critical problem in war veterans. Combat veterans are not only more likely to have suicidal ideation, often associated with PTSD and depression, but they are more likely to act on a suicidal plan [52]. Citizen soldiers (National Guard and Reserves) represent approximately 40% of the two million armed forces deployed to Afghanistan and Iraq. Twenty-five to forty percent of them develop PTSD, clinical depression, sleep disturbances, or suicidal thoughts [53]. Veterans reporting subthreshold PTSD were three times more likely to endorse these markers of elevated suicide risk relative to the veterans without PTSD [54]. They found no significant differences in likelihood of endorsing hopelessness or suicidal ideation comparing subthres‐ hold and threshold PTSD groups, although the subthreshold PTSD group was less likely to report prior mental health treatment [54]. Major depressive disorder cooccurs frequently with PTSD, and both disorders are linked to suicidal ideation. For the war veterans with depression symptoms, there is a strong relation between PTSD symptoms and suicidal ideation. Accord‐ ing to these findings, when analyzing PTSD-diagnosed war veterans, depression symptoms of suicidal ideation must be taken into account [55]. Of those veterans diagnosed with PTSD, many have comorbid psychiatric disorders, typically major depressive disorder, substance use disorders, and other anxiety disorders [56]. Veterans with PTSD are also more likely to have social, occupational, and functional difficulties, including social isolation, frequent interper‐ sonal altercations, and suicidal ideation [28]. PTSD and MDD occur together frequently, and both disorders have been separately linked to the increased risk of suicidal ideation [57, 58]. It is unclear, however, whether the combination of comorbid MDD and PTSD confers an increased risk for suicidal ideation beyond the risk presented by either diagnosis alone. Several studies of veteran samples have found that the combination of PTSD and MDD did not place

individuals at greater risk for suicidal ideation than did a single diagnosis [54, 55, 59]. Conversely, Oquendo et al. [60] found that individuals with current MDD and comorbid PTSD were more likely to endorse suicidal ideation compared to those without a current PTSD diagnosis. In a different study, it was determined that among veterans with schizophrenia and schizoaffective disorder, there is an independent relation between comorbid PTSD suicidal ideation risk but no such risk could be detected for suicide attempt [61]. Suicide has huge effect on public health but despite efficient interventions, a great number of people with suicide risk cannot benefit from these interventions and lose their lives. Until now, a huge number of programs and strategies named as "suicide prevention" have been developed. Recent inter‐ ventions about exercise give hope in the prevention of suicide thanks to its ease of application because exercise mitigates depression symptoms. Alleviating depression symptoms may provide lessened suicidal ideation and attempt but no study has so far indicated a direct relation between exercise and suicidal behavior. Davidson et al. [62] analyzed in veteran sampling a number of variables (sleep disorders, PTSD, and depression) that might be associated with suicidal risk. In this study, it has been emphasized that there may exist an indirect relation between exercise and suicide. It has also been suggested that exercise is also connected with low depression symptoms and a better sleep pattern, which might in effect lead to lower suicidal risk. A high prevalence of all types of violence is associated with the highest prevalence of depression and PTSD [63]. It is well established that intimate male partner violence (IPV) has a high impact on women's mental health. Compared to women in control group, among women subjected to physical and psychological IPV, there is higher ratio of depression and anxiety disorders, PTSD, and suicidal ideation. Among women exposed to sexual abuse and sexual violence, there is high ratio of depression symptoms, physical/ psychological abuse, and suicide attempt. In reality, PTSD on its own is quite hard to see. Depression symptoms are present either singly or codiagnosed with PTSD. Anxiety ratios are higher among women with comorbidite or abused women with depression symptoms. This may explain the high ratio of suicide attempts and anxiety among physically/psychologically abused women [64, 65]. Recovery from depressive symptoms, state anxiety, and posttraumatic stress disorder in women exposed to physical and psychological but not to psychological intimate partner violence alone. A metaanalysis with 50-article examining the relation among PTSD and past and present suicidal ideation and behavior has been conducted. There is no evidence showing that among PTSD patients there is a risk for completed suicide risk. A relation has been found among presuicide attempt and past and present suicidal ideation. Upon checking other psychiatric disorders (including depression), the relation between PTSD and suicide attempt has been examined but no sufficient data could be detected, but it was also reported that comorbidity depression and pretraumatic psychiatric state may have been a mediator. It is seen that a relation exists among various factors and PTSD and suicidal tendency [66]. In a different study, it was seen that among women patients with comorbid PTSD and drug addiction, suicide behavior varies according to drug addiction type and presence of preventive factors (for instance, worries about kids, will to live, and coping skill) [67]. Clinicians should be attentive to suicide risk in returned veterans and in women exposed to physical/psychological and psychological IPV. For future studies, assessing suicide risk in PTSD and identifying risk factors shall assist in better understanding the topic and preventing suicidal behavior.

ideation could be detected [24, 47]. For example, Warshaw et al. [24] reported that there was no association between PD and suicidal ideation after controlling for common comorbid psychiatric disorders. In another study, it was revealed that suicidal behavior risk in panic disorder is not higher than the risk in major depressive disorder [42]. Dammen et al. [47] could not find any difference in terms of suicidal ideation between patients with or without panic disorder. Several mental disorders, such as personality disorders, and life events that that have been associated with suicidality, e.g., early childhood abuse, were not assessed and may account partially for the observed association between PD and suicidal ideation [48, 49]. In some clinical studies, patients with PD and borderline personality disorder were at signifi‐ cantly higher risk of suicidal behavior than were PD patients with panic disorder alone [24]. To sum up, there is still an ongoing discussion about the relation between panic disorder and suicide behavior. It is not yet identified if panic disorder singly or when comorbid with other mental disorders like major depressive disorder is effective in suicidal behavior [24, 40, 50]. Thus, the data indicate that the risk of suicide in panic disorder is substantial. As a consequence, clinicians should alert themselves to this preventable outcome and approach treatment with

Posttraumatic stress disorder (PTSD) is frequently associated with suicidal ideation and suicide attempts. Suicide is an important cause of death in veterans, and the risk for intentional death continues to be high many years after service [51]. Suicidal behavior is a critical problem in war veterans. Combat veterans are not only more likely to have suicidal ideation, often associated with PTSD and depression, but they are more likely to act on a suicidal plan [52]. Citizen soldiers (National Guard and Reserves) represent approximately 40% of the two million armed forces deployed to Afghanistan and Iraq. Twenty-five to forty percent of them develop PTSD, clinical depression, sleep disturbances, or suicidal thoughts [53]. Veterans reporting subthreshold PTSD were three times more likely to endorse these markers of elevated suicide risk relative to the veterans without PTSD [54]. They found no significant differences in likelihood of endorsing hopelessness or suicidal ideation comparing subthres‐ hold and threshold PTSD groups, although the subthreshold PTSD group was less likely to report prior mental health treatment [54]. Major depressive disorder cooccurs frequently with PTSD, and both disorders are linked to suicidal ideation. For the war veterans with depression symptoms, there is a strong relation between PTSD symptoms and suicidal ideation. Accord‐ ing to these findings, when analyzing PTSD-diagnosed war veterans, depression symptoms of suicidal ideation must be taken into account [55]. Of those veterans diagnosed with PTSD, many have comorbid psychiatric disorders, typically major depressive disorder, substance use disorders, and other anxiety disorders [56]. Veterans with PTSD are also more likely to have social, occupational, and functional difficulties, including social isolation, frequent interper‐ sonal altercations, and suicidal ideation [28]. PTSD and MDD occur together frequently, and both disorders have been separately linked to the increased risk of suicidal ideation [57, 58]. It is unclear, however, whether the combination of comorbid MDD and PTSD confers an increased risk for suicidal ideation beyond the risk presented by either diagnosis alone. Several studies of veteran samples have found that the combination of PTSD and MDD did not place

added caution.

108 A Fresh Look at Anxiety Disorders

**5.2. Posttraumatic stress disorder and suicide**

#### **5.3. Obsessive-compulsive disorder and suicide**

Suicidal thoughts and behaviors, also known as suicidality, are a fairly neglected area of study in patients with obsessive-compulsive disorder. Patients with obsessive-compulsive disorder (OCD) have historically been considered at low risk for suicide, but recent studies are contro‐ versial. Torres et al. [68] found thirty-six percent of the patients reported lifetime suicidal thoughts, 20% had made suicidal plans, 11% had already attempted suicide, and 10% pre‐ sented current suicidal thoughts. The sexual/religious dimension and comorbid substance use disorders remained associated with suicidal thoughts and plans, while impulse-control disorders were associated with current suicidal thoughts and with suicide plans and attempts [68]. The risk of suicidal behaviors must be carefully investigated in OCD patients, particularly those with symptoms of the sexual/religious dimension and comorbid major depressive disorder, PTSD, substance use disorders, and impulse-control disorders [69]. Lester and Abdel-Khalek [70] reported that there is no relation between OCD and suicidal ideation but a relation between OCD and suicide attempt. However, there are certain limits such as the smallness of sampling group and failure to control depression. In a different study conducted with same research group in 2002, it was reported that there is a significant relation between OCD and suicidal ideation but again depression was not controlled in another study [71]. Obsessive-compulsive personality disorder is a factor increasing risk for nonfatal suicidal behavior independently of risk conferred by depressive disorders. For example, Diaconu and Turecki [72] reported that the comorbid obsessive-compulsive personality disorder depression group presented increased current and lifetime suicide ideation compared to the groups with depression alone or without depression, or personality disorders they also had increased history of suicide attempts which were often multiple attempts. OCD is associated with a high risk for suicidal behavior. Depression and hopelessness are the major correlates of suicidal behavior [73]. Suicidal behavior is not a common phenomenon in OCD, but among single patients in particular, accompanying depression, symmetry/order obsession, and compulsions are high risk factors for suicide [74]. In patients with OCD, risk factors for suicidal behavior have been left ignored when compared to other anxiety disorders. However, a high ratio as 10–27% was reported for suicidal behavior. This condition shows that OCD patients may commit suicide attempt at least once in their life [16]. Besides as in OCD assistance-seeking ratio is comparatively lower than assistance search in comorbid OCD, it becomes evident that in OCD patients assistance-seeking methods should be increased in suicide prevention strategies. Suicidality has been underestimated in OCD and should be investigated in every patient, so that appropriate preventive measures can be taken.

#### **5.4. Generalized anxiety disorder and suicide**

Generalized anxiety disorder (GAD) is a chronic general disease among adult population but it is comparatively a less understood clinical state. Clinicians may have knowledge about the characteristics of GAD such as over anxiety, anxiety, and hypervigilance, but such symptoms may fall short in distinguishing GAD from other psychiatric disorders, because in the course of several mental diseases these symptoms are frequently observed. Interestingly enough, despite the changes in diagnosis criteria, prevalence predictions for GAD are quite consistent among epidemiologic studies. It is predicted that among general population, lifelong preva‐ lence is 5% (DSM-III and/or DSM-IV-R criteria). GAD is common in different levels among gender, ethnics, and social groups. Among age 40 and above women, in addition to high ratio as 10%, in the cases applying to primary care service, GAD is 8%. Again in the first primary care service, GAD is the most widely diagnosed anxiety disorder. GAD's age of onset is different than other anxiety disorders. Prevalence ratios are low among teenagers and young adults but age is a remarkably triggering effect. Women are, compared to men, at higher risk. GAD is more frequent among unemployed housewives with chronic medical diseases [75]. GAD is frequently associated with accompanying depression, other anxiety, and somatoform disorders [76]. Weak family relations, codiagnosed C group personality disorders in stressful life events and codiagnosed Axis 1 disorders, are the increasing factors of GAD's effects [77]. GAD is quite prevalent all over the world but the relation between GAD and suicidal behavior has not been investigated. There are a limited number of studies on this topic. In another study, it was detected that there is a relation between impairment and suicidal ideation and GAD [29]. Zimmerman and Chelminski [78] found that depressed patients with GAD had higher levels of suicidal ideation when compared to patients with depression only. In future studies, analyzing the impact of GAD on suicidal behavior may be illuminating on the potential risk factors.

#### **5.5. Social anxiety disorder (social phobia) and suicide**

**5.3. Obsessive-compulsive disorder and suicide**

110 A Fresh Look at Anxiety Disorders

patient, so that appropriate preventive measures can be taken.

Generalized anxiety disorder (GAD) is a chronic general disease among adult population but it is comparatively a less understood clinical state. Clinicians may have knowledge about the characteristics of GAD such as over anxiety, anxiety, and hypervigilance, but such symptoms may fall short in distinguishing GAD from other psychiatric disorders, because in the course of several mental diseases these symptoms are frequently observed. Interestingly enough, despite the changes in diagnosis criteria, prevalence predictions for GAD are quite consistent

**5.4. Generalized anxiety disorder and suicide**

Suicidal thoughts and behaviors, also known as suicidality, are a fairly neglected area of study in patients with obsessive-compulsive disorder. Patients with obsessive-compulsive disorder (OCD) have historically been considered at low risk for suicide, but recent studies are contro‐ versial. Torres et al. [68] found thirty-six percent of the patients reported lifetime suicidal thoughts, 20% had made suicidal plans, 11% had already attempted suicide, and 10% pre‐ sented current suicidal thoughts. The sexual/religious dimension and comorbid substance use disorders remained associated with suicidal thoughts and plans, while impulse-control disorders were associated with current suicidal thoughts and with suicide plans and attempts [68]. The risk of suicidal behaviors must be carefully investigated in OCD patients, particularly those with symptoms of the sexual/religious dimension and comorbid major depressive disorder, PTSD, substance use disorders, and impulse-control disorders [69]. Lester and Abdel-Khalek [70] reported that there is no relation between OCD and suicidal ideation but a relation between OCD and suicide attempt. However, there are certain limits such as the smallness of sampling group and failure to control depression. In a different study conducted with same research group in 2002, it was reported that there is a significant relation between OCD and suicidal ideation but again depression was not controlled in another study [71]. Obsessive-compulsive personality disorder is a factor increasing risk for nonfatal suicidal behavior independently of risk conferred by depressive disorders. For example, Diaconu and Turecki [72] reported that the comorbid obsessive-compulsive personality disorder depression group presented increased current and lifetime suicide ideation compared to the groups with depression alone or without depression, or personality disorders they also had increased history of suicide attempts which were often multiple attempts. OCD is associated with a high risk for suicidal behavior. Depression and hopelessness are the major correlates of suicidal behavior [73]. Suicidal behavior is not a common phenomenon in OCD, but among single patients in particular, accompanying depression, symmetry/order obsession, and compulsions are high risk factors for suicide [74]. In patients with OCD, risk factors for suicidal behavior have been left ignored when compared to other anxiety disorders. However, a high ratio as 10–27% was reported for suicidal behavior. This condition shows that OCD patients may commit suicide attempt at least once in their life [16]. Besides as in OCD assistance-seeking ratio is comparatively lower than assistance search in comorbid OCD, it becomes evident that in OCD patients assistance-seeking methods should be increased in suicide prevention strategies. Suicidality has been underestimated in OCD and should be investigated in every

Life-long prevalence of social anxiety disorder is 13%, which is a quite high ratio among general public. Not only it leads to a major loss of ability but it is often associated with increased suicide ratios and codiagnosed drug abuse; but the relation between social anxiety disorder and suicidal behaviors has not been analyzed adequately so far. The characteristics of patients with social anxiety disorder are that they unrealistically fear that others will constantly and persistently criticize their acts. Social anxiety disorder usually springs up during puberty and it really emerges for the first time after age 25 [79]. Rates of social anxiety disorder were highest among women and persons who were younger, less educated, single, and of lower socioeco‐ nomic class. SAD is a common illness often followed by comorbid MDD and alcohol depend‐ ence. SAD with comorbid MDD predicts a substantially elevated risk of alcohol dependence and suicide-related symptoms, stressing the need for early SAD detection [80]. It has been reported that despite the high frequency of suicidal ideation among patients with anxiety disorder, the level of suicide attempt is low. Furthermore, the data show that in social anxiety disordered cases, the ratio of lifelong suicide attempt is 12–18% but this condition is associated with codiagnosed depression symptoms [81]. It is also reported that 69% of patients with social anxiety disorder are afflicted with other lifelong comorbid mental disorders and with the occurrence of social anxiety usually, they are added into clinical picture. Once contrasted with people having no mental disorder, uncomplicated social anxiety disorder is found to be connected with increased suicidal ideation, financial dependency, and having sought medical treatment. Nonetheless, no connection was established between social anxiety disorder and suicide attempt and psychiatric treatment. It has been reported that in social anxiety disorder there is elevated suicide attempts, but these cases are surprisingly comorbid cases. In the absence of comorbidity, social anxiety disorder is still a problem that spoils the functionality, but patients rarely seek psychiatric treatment; hence large numbers of cases cannot be examined well by the clinicians [82]. The effect of anxiety disorder alone on suicide behavior has not yet been established but when social anxiety disorder's chronic course and adverse impact on functionality are considered, particular attention needs to be paid in the assessment of patients in this group.

Comparison of the suicidal behaviors of the specific anxiety disorders is given in Table 1.


**Table 1.** Specific anxiety disorders and suicidal behaviors

### **6. The comorbidity of anxiety disorders in other illnesses and suicide**

Anxiety disorders, when accompanied with other comorbid mental disorders, may affect the course and treatment of disease. Comorbid conditions may occasionally lead to diagnostic ambiguity, and in a number of cases, multiple comorbid mental disorder may accompany the present clinical picture. In a research conducted by Sanderson et al. [83], it was reported that among 70% of patients with anxiety disorder, there is minimum one additional Axis 1 diagnosis. In present study, the highness of comorbidity ratio draws attention. However, once considered that current diagnosis systems are largely consisting of joint symptom clusters, these ratios appear to be exaggerated predictions. Nevertheless, mental disorder comorbidity is considered negative for the natural course of illness by implying additional kinds of dysfunction depending on whether it is a disorder of mood, substance abuse, or personality [84, 85]. These three are the most common comorbid disorders.

#### **6.1. The comorbidity of anxiety disorders in mood disorders and suicide**

The potential association between anxiety disorders and suicidal ideation rendered mixed results. In the researches, positive findings between anxiety and suicidal ideation may be connected to accompanying depression. In patients diagnosed with anxiety disorder not positing mood disorder story, there was no increased risk for suicidal ideation. On the other hand, in a recent study, it has been reported that among anxiety disordered cases not accom‐ panied with mood disorder, there is an increased risk for suicidal ideation [86]. Nonetheless, in current research, subsyndromic depression symptoms have not been excluded, which puts the findings of research open to discussion. Traditionally, research on suicide has emphasized relationships with mood disorders, psychotic disorders, and some personality disorders. Although certain features of anxiety have been incorporated into models of suicide, anxietyrelated conditions such as severe psychic anxiety, agitation, and panic have typically been examined as predictors of suicidal behaviors only to the extent that they overlap with mood disorders. Sareen et al. [16] in their 3-year long monitoring studies probed into the relation between anxiety and mood disorder–diagnosed cases and lifelong suicide ideation and suicide attempt, and they found out that in the presence of an anxiety disorder not positing a mood disorder story, there is a significant relation between lifelong suicidal ideation and suicide attempt. However, the main limitation of their study is that while analyzing particular anxiety disorders, probable mixing factors (syndromal depressive symptoms, etc.) have not been excluded. Despite this, there is fairly strong evidence that even subthreshold depressive symptoms are associated with increased psychosocial impairment, higher rates of comorbid substance use problems, and greater risk for future syndromal depressive episodes [87]. Further, studies provide strong evidence for an additive and interactive relative risk conveyed by cooccurring anxiety and depression. Consequently, comprehensive suicide assessment plans are strongly recommended when evaluating or treating individuals with an anxiety disorder, and especially individuals with comorbid anxiety and depressive disorders [88].

#### **6.2. The comorbidity of anxiety disorders in bipolar disorder and suicide**

but patients rarely seek psychiatric treatment; hence large numbers of cases cannot be examined well by the clinicians [82]. The effect of anxiety disorder alone on suicide behavior has not yet been established but when social anxiety disorder's chronic course and adverse impact on functionality are considered, particular attention needs to be paid in the assessment

Comparison of the suicidal behaviors of the specific anxiety disorders is given in Table 1.

+/? ? ?

? ? ?

**6. The comorbidity of anxiety disorders in other illnesses and suicide**

Anxiety disorders, when accompanied with other comorbid mental disorders, may affect the course and treatment of disease. Comorbid conditions may occasionally lead to diagnostic ambiguity, and in a number of cases, multiple comorbid mental disorder may accompany the present clinical picture. In a research conducted by Sanderson et al. [83], it was reported that among 70% of patients with anxiety disorder, there is minimum one additional Axis 1 diagnosis. In present study, the highness of comorbidity ratio draws attention. However, once considered that current diagnosis systems are largely consisting of joint symptom clusters, these ratios appear to be exaggerated predictions. Nevertheless, mental disorder comorbidity is considered negative for the natural course of illness by implying additional kinds of dysfunction depending on whether it is a disorder of mood, substance abuse, or personality

The potential association between anxiety disorders and suicidal ideation rendered mixed results. In the researches, positive findings between anxiety and suicidal ideation may be

Panic disorder ++++ ++++ ?

disorder +++ +++ ?

Social anxiety disorder ? ? ?

Simple phobia ? ? ?

Strong evidence: ++++, Evidence: +++, No clear evidence +/?, No data: ?

[84, 85]. These three are the most common comorbid disorders.

**6.1. The comorbidity of anxiety disorders in mood disorders and suicide**

**Table 1.** Specific anxiety disorders and suicidal behaviors

**Suicide ideation Suicide attempt Completed suicide**

of patients in this group.

112 A Fresh Look at Anxiety Disorders

**Specific anxiety disorders**

Posttraumatic stress

Obsessive-compulsive

Generalized anxiety

disorder

disorder

Clinical and epidemiological studies have provided convincing evidence that comorbid anxiety disorders are relatively prevalent among patients with bipolar disorder (BD), found in up to 65% of cases [89]. Henry et al. [90] studied 318 inpatients including bipolar I and found that 24% had at least one lifetime anxiety disorder and 11% of the patients had more than one such disorder. Comorbidity of anxiety disorders may be associated with greater suicidality, substance abuse, resistance to pharmacological treatment, and poor outcome [91-93]. Altındag et al. [94] studied 70 outpatients including bipolar I and found that 27.1% had at least one lifetime anxiety disorder, and most common anxiety disorders in this sample were obsessivecompulsive disorder (12.8%) and specific phobia (12.8%), followed by panic disorder (5.7%). Anxiety disorder comorbidity appears to be associated with greater number of hospitaliza‐ tions, psychotic symptoms, and suicide attempts in patients with bipolar disorder type I. Bipolar subjects with anxiety disorders were younger, had earlier age at onset of illness, and were overrepresented by female subjects and those with earlier onset illness compared to those without anxiety disorder [95]. Panic disorder, which also confers an independent risk of suicide and psychiatric comorbidity, in general has been found to amplify suicidality in mooddisordered patients [96]. The presence of comorbid panic disorder in individuals with bipolar disorder may confer an increased risk of suicide risk. Some papers' reviewed have conflicting conclusions but the majority of papers support an increased risk. Future research should study specific bipolar subgroups, focus on anxiety and panic symptoms rather than diagnosis, and look at the role of specific pharmacological treatment in patients with comorbid mood and anxiety disorders. Among anxiety disorders, only social phobia (SP) was significantly associ‐ ated with history of suicide attempt in BD. In other words, SP is an important risk factor for suicidal behavior in BD [97]. Suicide takes significantly different forms within different stages of behavioral bipolar disorder. Suicide attempts and suicidal ideation have been found to be most closely connected to the depressive periods of disease. Severity of despair and depression are the key indicators of risk for all stages [98]. Previous studies have shown a significant relationship between suicide ideation and mixed depression. The rates of mixed depression among bipolar and nonbipolar depressive suicide attempters were much higher than previ‐ ously reported among nonsuicidal bipolar II and unipolar depressive outpatients, suggesting that suicide attempters come mainly from mixed depressives with predominantly bipolar II base. Irritability and psychomotor agitation were the strongest predictors of suicide attempt [99]. Although anxiety may be a modifiable suicide risk factor among bipolar patients, anxiety disorder comorbidity has not been highlighted as critical in identification of high-risk indi‐ viduals nor has its treatment been integrated into suicide prevention strategies. Although lifelong anxiety disorders are related to past suicide attempts, current comorbid anxiety disorders are found to be connected to suicidal ideation. In anxiety disordered individuals, suicidal ideation is a risk factor for suicide behaviors in future. The early onset of polar disorder and frequent appearance of rapid cycling and mixed periods constitute great risk for suicidal behavior. All in all, both bipolar disorder and anxiety disorder bear risks for suicidal behavior. In the presence of comorbid anxiety disorders, suicide behavior risk may gain even further impetus in bipolar disorder cases. To put differently, anxiety disorders (social anxiety disorder at most) may play active role in developing suicidal ideation and suicide attempt among bipolar disordered cases [100]. In the presence of comorbid anxiety disorders in bipolar disordered cases, patients must be attentively monitored against suicidal risk. Further studies shall contribute to better comprehending suicide behavior in bipolar disorder patients with anxiety disorder.

#### **6.3. The comorbidity of anxiety disorders in substance abuse and suicide**

The high prevalence of comorbid drug abuse in anxiety disorders is attributed to patients' relief seeking in alcohol and/or drugs for alleviating the emotional stress they cope with (selfmedication). Regardless of the high ratios of alcohol and drug use in anxiety disorders, selfmedication has been discussed in limited numbers of studies. Likewise although in mood disorders there is high frequency of alcohol and drug abuse, there is a limited body of research on this domain. The use of alcohol and drugs to relieve affective symptoms is common among individuals with mood disorders in the general population [101]. Comorbid specific mood and anxiety disorders and specific drug use are widely common in American society. Among women in particular comorbid psychiatric disorders may lead to critical use of illegal drugs. In present study, it was reported that among female cases diagnosed with comorbid mood and anxiety disorder, in comparison to postdrug-alcohol addicted men, medical prognosis of disease is affected more negatively [102]. Among cases with anxiety disorder self-medication has been associated with accompanying mood disorders, drug abuse, anxiety, suicidal ideation, and increased risk for suicide attempt. Even after controlling sociodemographic and psychiatric variances self-medication remained to be related to suicidal ideation and increased risk for suicide attempt. Bolton et al. [103] reported that individuals with anxiety disorders who self-medicate their symptoms with alcohol or drugs may be at increased risk for mood and substance use disorders and suicidal behavior. In this study covering a wide sampling of society, self-medication prevalence varied between 7.9% (social phobia and speech subtype) and 35.6% (GAD). Multivariate analyses put forth that self-medication is independently related to lifelong suicidal ideation and attempts and also to an increased comorbid mood disorder and drug abuse tendency. Alcohol use disorders and suicidal ideation cooccur, yet few studies have investigated the risk and protective factors that influence their comorbidity. The comorbidity between alcohol use disorders and suicidal ideation is characterized in young women by cooccurring psychopathology, drinking to cope, and negative life events [104].

#### **6.4. The comorbidity of anxiety disorders in schizophrenia and suicide**

specific bipolar subgroups, focus on anxiety and panic symptoms rather than diagnosis, and look at the role of specific pharmacological treatment in patients with comorbid mood and anxiety disorders. Among anxiety disorders, only social phobia (SP) was significantly associ‐ ated with history of suicide attempt in BD. In other words, SP is an important risk factor for suicidal behavior in BD [97]. Suicide takes significantly different forms within different stages of behavioral bipolar disorder. Suicide attempts and suicidal ideation have been found to be most closely connected to the depressive periods of disease. Severity of despair and depression are the key indicators of risk for all stages [98]. Previous studies have shown a significant relationship between suicide ideation and mixed depression. The rates of mixed depression among bipolar and nonbipolar depressive suicide attempters were much higher than previ‐ ously reported among nonsuicidal bipolar II and unipolar depressive outpatients, suggesting that suicide attempters come mainly from mixed depressives with predominantly bipolar II base. Irritability and psychomotor agitation were the strongest predictors of suicide attempt [99]. Although anxiety may be a modifiable suicide risk factor among bipolar patients, anxiety disorder comorbidity has not been highlighted as critical in identification of high-risk indi‐ viduals nor has its treatment been integrated into suicide prevention strategies. Although lifelong anxiety disorders are related to past suicide attempts, current comorbid anxiety disorders are found to be connected to suicidal ideation. In anxiety disordered individuals, suicidal ideation is a risk factor for suicide behaviors in future. The early onset of polar disorder and frequent appearance of rapid cycling and mixed periods constitute great risk for suicidal behavior. All in all, both bipolar disorder and anxiety disorder bear risks for suicidal behavior. In the presence of comorbid anxiety disorders, suicide behavior risk may gain even further impetus in bipolar disorder cases. To put differently, anxiety disorders (social anxiety disorder at most) may play active role in developing suicidal ideation and suicide attempt among bipolar disordered cases [100]. In the presence of comorbid anxiety disorders in bipolar disordered cases, patients must be attentively monitored against suicidal risk. Further studies shall contribute to better comprehending suicide behavior in bipolar disorder patients with

**6.3. The comorbidity of anxiety disorders in substance abuse and suicide**

The high prevalence of comorbid drug abuse in anxiety disorders is attributed to patients' relief seeking in alcohol and/or drugs for alleviating the emotional stress they cope with (selfmedication). Regardless of the high ratios of alcohol and drug use in anxiety disorders, selfmedication has been discussed in limited numbers of studies. Likewise although in mood disorders there is high frequency of alcohol and drug abuse, there is a limited body of research on this domain. The use of alcohol and drugs to relieve affective symptoms is common among individuals with mood disorders in the general population [101]. Comorbid specific mood and anxiety disorders and specific drug use are widely common in American society. Among women in particular comorbid psychiatric disorders may lead to critical use of illegal drugs. In present study, it was reported that among female cases diagnosed with comorbid mood and anxiety disorder, in comparison to postdrug-alcohol addicted men, medical prognosis of disease is affected more negatively [102]. Among cases with anxiety disorder self-medication has been associated with accompanying mood disorders, drug abuse, anxiety, suicidal

anxiety disorder.

114 A Fresh Look at Anxiety Disorders

Among schizophrenic patients, there is a considerably high ratio of suicidal behavior. It is particularly noteworthy that among schizophrenic cases with suicide attempt story and suicidal ideation in the past, there is also comorbid OCD. Also the ones with suicide story are significantly higher in patients with OCD-schizophrenia than in patients with non-OCD schizophrenia. Compulsive symptoms were significant predictors of suicide attempt among patients with schizophrenia [105]. The obsessive-compulsive symptoms may account for the emergence of suicidality in patients with OCD-schizophrenia. In schizophrenia suicidal ideation has been auspicated with depressive mood, anxiety, low self esteem, negative disease perceptions, negative assessments of the self and others, and daily alcohol consumption. The frequency of coping with audio hallucinations and delusions has no connection with suicidal ideation but distress caused by positive symptoms was found to be related to suicidal ideation [106]. Affective dysfunction, including distress in response to hallucinations and delusions, was a key factor associated with suicidal ideation in individuals with psychotic relapse.

#### **6.5. The comorbidity of anxiety disorders in major depression and suicide**

In elderly persons with major depressive disorder, coexisting generalized anxiety disorder or panic disorder is associated with more severe symptoms and poorer short-term treatment outcomes. De Luca et al. [107] found evidence that comorbid generalized anxiety disorder or panic disorder is associated with a greater decline in memory in late-life MDD and suicidal ideation. The clinical correlates of comorbid anxiety and depression in a sample of older patients with major depression. In elderly patients with anxious depression, psychosocial support and suicidal ideation should be assessed [108]. Anxiety symptoms are the frequent comorbids of old-age depression; hence MDB comorbid with subsyndromal anxiety symptoms is termed as "anxious depression." In reality, MDD is generally comorbid with specific anxiety disorders but there is no definite information on the frequency, diagnosis, clinical course, and treatment approaches for anxiety disorders among elderly group. It is acknowledged that specific anxiety disorders, anxiety disorders comorbid with MDD, are less common among the elderly. Still, in aged people with anxious depression, particularly in complex cases comorbid with chronic physical disease, there is a heightened risk for suicidal ideation, disability, and poor prognosis. Standard pharmacotherapy could be sufficient for depression but among many older people with anxious depression. Standard pharmacotherapy on its own may fail to be sufficient. There are a number of psychosocial treatments but they are not specific for old-age anxious depression. However, psychosocial interventions may be a major constit‐ uent in the treatment of these patients [109]. In the elderly group, ratios of completed suicide are significantly higher than the other age groups, thus in preventing old-age suicides, the elderly cases diagnosed with "anxious depression" must be studied attentively.

#### **6.6. The comorbidity of anxiety disorders in physical illness and suicide**

Suicidal ideation and behavior have been associated with a variety of neurological illnesses. There are important linkages between suicidal ideation and behavior and neurological conditions, including epilepsy, multiple sclerosis, and amyotrophic lateral sclerosis [110]. Anxiety disorders are common in patients with multiple sclerosis, but are frequently over‐ looked and undertreated. Korostil and Feinstein [111] studied 140 outpatients including multiple sclerosis and found that 35.7% had at least one lifetime anxiety disorder, and most common anxiety disorders in this sample were panic disorder (10%) and obsessive-compulsive disorder (8.6%), followed by generalized anxiety disorder (18.6%). Subjects with an anxiety disorder were more likely to be female, have a history of depression, drink to excess, report higher social stress, and have contemplated suicide. Risk factors include being female, a comorbid diagnosis of depression, and limited social support. Clinicians should evaluate all multiple sclerosis subjects for anxiety disorders, as they represent a treatable cause of disability in multiple sclerosis. The studies have observed a strong relationship between coronary artery disease (CAD) and psychiatric disorder, notably depression, anxiety, and panic attacks. A significant positive relation was observed between CAD and lifelong prevalence of suicide attempts. Suicide attempts were found to be connected with major depression and comorbid anxiety disorder but no relation was detected between suicide attempts and anxiety singly. At the end of logistic regression analysis, the relation between suicide attempt and CAD contin‐ ued after making correction for depression and anxiety. In a different saying, CAD is an independent risk factor more powerful than depression for suicide behavior [112]. Acne is a common disease in adolescence with female preponderance. It could cause poor self-esteem and social phobia. Previous studies based on questionnaires from several thousands of adolescents showed that acne is associated with major depression and suicide [113, 114]. However, the gender- and age-specific risk of depression and suicide in patients with acne remain largely unknown. The risk is additive in women with acne. Similar additive risk of suicide was noticed in women with acne. In recently, Yang et al. [115] reported that acne and gender, independently and jointly, were associated with major depression and suicide. Special medical support should be warranted in females with acne for the risk of major depression and suicide. It has been demonstrated that a correlation exists between an extensive scope of physical diseases and increased ratios of suicide. As the studies on particular topic are examined, it surfaces that medical diagnoses alone are not sufficient causes to lead a person to suicide. Comorbid mental disorders are equally responsible in the development of suicide. It is thus important to train the clinicians on identifying not only physical symptoms but mental symptoms too and the ways to determine their effects on the treatment and the course of disease. To have a lifesaving effect, particular attention to crisis periods, stages of physical illness, and postdischarge period should be monitored attentively on accounts of being riskposing periods for suicide behavior. It is thus obviously crucial to monitor physically sick patients to stay alert against suicide behavior.

#### **6.7. The comorbidity of anxiety disorders in personality disorders and suicide**

comorbid with chronic physical disease, there is a heightened risk for suicidal ideation, disability, and poor prognosis. Standard pharmacotherapy could be sufficient for depression but among many older people with anxious depression. Standard pharmacotherapy on its own may fail to be sufficient. There are a number of psychosocial treatments but they are not specific for old-age anxious depression. However, psychosocial interventions may be a major constit‐ uent in the treatment of these patients [109]. In the elderly group, ratios of completed suicide are significantly higher than the other age groups, thus in preventing old-age suicides, the

Suicidal ideation and behavior have been associated with a variety of neurological illnesses. There are important linkages between suicidal ideation and behavior and neurological conditions, including epilepsy, multiple sclerosis, and amyotrophic lateral sclerosis [110]. Anxiety disorders are common in patients with multiple sclerosis, but are frequently over‐ looked and undertreated. Korostil and Feinstein [111] studied 140 outpatients including multiple sclerosis and found that 35.7% had at least one lifetime anxiety disorder, and most common anxiety disorders in this sample were panic disorder (10%) and obsessive-compulsive disorder (8.6%), followed by generalized anxiety disorder (18.6%). Subjects with an anxiety disorder were more likely to be female, have a history of depression, drink to excess, report higher social stress, and have contemplated suicide. Risk factors include being female, a comorbid diagnosis of depression, and limited social support. Clinicians should evaluate all multiple sclerosis subjects for anxiety disorders, as they represent a treatable cause of disability in multiple sclerosis. The studies have observed a strong relationship between coronary artery disease (CAD) and psychiatric disorder, notably depression, anxiety, and panic attacks. A significant positive relation was observed between CAD and lifelong prevalence of suicide attempts. Suicide attempts were found to be connected with major depression and comorbid anxiety disorder but no relation was detected between suicide attempts and anxiety singly. At the end of logistic regression analysis, the relation between suicide attempt and CAD contin‐ ued after making correction for depression and anxiety. In a different saying, CAD is an independent risk factor more powerful than depression for suicide behavior [112]. Acne is a common disease in adolescence with female preponderance. It could cause poor self-esteem and social phobia. Previous studies based on questionnaires from several thousands of adolescents showed that acne is associated with major depression and suicide [113, 114]. However, the gender- and age-specific risk of depression and suicide in patients with acne remain largely unknown. The risk is additive in women with acne. Similar additive risk of suicide was noticed in women with acne. In recently, Yang et al. [115] reported that acne and gender, independently and jointly, were associated with major depression and suicide. Special medical support should be warranted in females with acne for the risk of major depression and suicide. It has been demonstrated that a correlation exists between an extensive scope of physical diseases and increased ratios of suicide. As the studies on particular topic are examined, it surfaces that medical diagnoses alone are not sufficient causes to lead a person to suicide. Comorbid mental disorders are equally responsible in the development of suicide. It is thus important to train the clinicians on identifying not only physical symptoms but mental

elderly cases diagnosed with "anxious depression" must be studied attentively.

**6.6. The comorbidity of anxiety disorders in physical illness and suicide**

116 A Fresh Look at Anxiety Disorders

A comprehensive metaanalysis to identify the proportions of comorbid personality disorders (PD) across the major subtypes of anxiety disorders has not previously been published. Friborg et al. [85] reported that the rate of any comorbid PD was high across all anxiety disorders. The findings reveal that Group C personality disorders are two times more common compared to Group A and B personality disorders, and within Group C personality disorders, the highest ratio was seen in avoidant PD, followed alternately by obsessive-compulsive and the depend‐ ent personality disorder. In cases where personality disorders are codiagnosed with anxiety disorders, the course and treatment response of the disease may alter. It has, for instance, been reported that in social anxiety disorder where PTSD provides a heterogeneous clinical picture, there is a high ratio of comorbid with avoidant PD. Except early onset, avoidant PD rendered insignificant or minor impacts on social anxiety disorder. No relation could be established between gender or length of anxiety disorder and personality disorder comorbidity. Patients with social phobia (61%) and generalized anxiety disorder (49%) were most often diagnosed with a personality disorder. Patients with simple phobia were rarely diagnosed with a personality disorder (12%) [83]. In a different study, it has been illustrated that present or lifelong panic disorders are related with borderline, avoidant, and dependent personality disorders; social anxiety disorder connected with avoidant personality disorder; and obses‐ sive-compulsive disorder associated with obsessive-compulsive and avoidant personality disorders. In anxiety disorders comorbid with personality disorders, unlike anxiety disorders with no personality disorder, there has been a more chronic course, increased suicidal behavior, and low level of functionality [116]. The relationship between cooccurring person‐ ality disorders and anxiety disorders (panic disorder with or without agoraphobia, social phobia, and generalized anxiety disorder) was examined, taking into account the effect of major depression. Generalized anxiety disorder, social phobia, and major depression were positively associated with the occurrence of one or more personality disorders, whereas panic disorder with agoraphobia was not associated [117]. The effect of comorbid personality disorders in obsessive-compulsive disorder is unclear. Baer and Jenike [118] in their research covering 96 OCD adult patients detected that in patients with mixed personality disorder, the length of OCD is longer compared to the ones with no OCD. The authors argued that the impacts of personality disorders on behavior and life style can be secondary OCD. The studies indicate that most individuals with OCD have comorbid personality disorders (PDs), partic‐ ularly from the anxious cluster. However, the nature and strength of this association remains unclear, as the majority of previous studies have relied heavily on clinical populations. Personality pathology is highly prevalent among people with OCD who are living in the community and should be routinely assessed, as it may affect help-seeking behavior and response to treatment [119]. Latas and Milovanovic [120] in a recent study proved that in anxiety disorder cases, personality disorders exhibit quite a high prevalence as 35% in posttraumatic stress disorder, 47% in panic disorder with agoraphobia and generalized anxiety disorder, 48% in social phobia, and 52% in OCD. In anxiety disorder cases, the highest ratio (39%) was found in Group C personality disorders. Also in samplings with personality disorders, high ratio of anxiety was detected particularly among borderline personality disorder cases. It is agreed that borderline personality disorder is a high risk factor for recurrent suicidal behavior. Personality disorders comorbid with anxiety disorder display a number of clinical outcomes such as suicide risk and more severe and less treatable anxiety disorders, thereby clinicians should place particular emphasis on identifying potential personality disorders in patients with anxiety disorder. Further studies should focus on the causes and risk factors for suicidal behavior particularly in patients with anxiety disorders comorbid with personality disorders.

### **7. Treatment studies**

The basic principles of treatment of anxiety disorders in major depression involve longer treatment and higher doses than are usually required for major depression. The impact of psychosocial disability and severity of depressive symptoms can be ameliorated with appro‐ priate treatment. Screening for depressive symptoms as well as administering an appropriate therapy seems the best way to prevent suicide attempts [121]. Newer treatments, such as the combination of psychotherapy and pharmacotherapy, may prove to be of greatest benefit for individuals with comorbidity of anxiety disorders in psychiatric disorders [122]. For the recent 25 years, much progress has been made in the treatment of five specific anxiety disorders such as social phobia, obsessive-compulsive disorder, generalized anxiety disorder, and posttrau‐ matic stress disorder. Placebo-controlled evidences suggest that pharmacological and psy‐ chological treatments offer substantially effective solutions [21, 123]. Treatment of anxiety disorders involve antidepressants (selective serotonin reuptake inhibitors (SSRI) mostly) and cognitive behavioral therapy. Among patients diagnosed with mood disorder and comorbid anxiety disorders, it is advisable to administer higher doses of SSRI [124]. Besides, a long-term discussion has been going on about the use of SSRIs (paroxetine, fluoxetine, and citalopram) which, as some argue, may have a triggering/stipulating effect on adult suicides since 1991 and children since 2002. Apter et al. [125] stated that paroxetine taking adult patients with major depression are at higher risk for suicidal ideation and behavior, and the same authors also claimed that there was no attempt in OCD and social phobia cases. In sync with this finding, the benefits of sertraline outweigh its potential risks in suicidal behavior among OCD patients, and OCD's effects are, in contrast to its effects in major depression, further positive [126]. In younger patients diagnosed with major depression, the risk of suicidal behavior uncovered with treatment is even higher. It is suggested that the rise in suicidal ideation and attempt parallel to the use of antidepressants is more risky for children and teenagers [21, 123]. Rickels et al. [127] in their two randomized controlled studies reported the positive effects of long-released venlafaxine on GAD. Among children and teenagers major depression and in GAD patients with venlafaxine, there might be a stage between suicidal behaviors and hostile behaviors. Antidepressant drugs play a vital role in the treatment of anxiety disorders and preventing suicidal behaviors among adult patients. Selective serotonin reuptake inhibi‐ tors are the first-line pharmacological treatment for these disorders, and that newer serotonin and norepinephrine reuptake inhibitors show significant promise, especially for comorbid cases. In the treatment of anxiety disorders, cognitive behavior therapy (CBT) can be applied in combination with pharmacotherapy or independently. For instance, in the treatment of panic disorder, CBT aims to control agoraphobic symptoms in panic disorders comorbid with agoraphobia, to inhibit adverse effect of medicine deduction and treatment and prevention of panic attacks. Not much study has been made on the effects of CBT applications in anxiety disorders on suicidal behavior, but when anxiety disorder cases are successfully treated with CBT there is likelihood to witness fewer ratios of suicide [128]. When anxiety disorders are comorbid with depression, disease symptoms are likely to be more severe; hence symptom severity should be taken into account while making treatment plan. Particularly speaking, patients diagnosed with panic disorder, PTSD, and comorbidity of anxiety disorders in major depression bear higher risks for suicide. The cases bearing potential risks for suicide should be kept and monitored under strict scrutiny by clinicians. In order to assess and monitor these patients, there is a need for relevant measurement tools of which reliability and validity tests have been confirmed. In suicide behavior treatment studies among anxiety disorders, ethic limitations have restricted the participation of individuals with acute suicidal tendency. In relevant studies, the lowness of suicidal behavior and restricted volume of samplings inhibited a precise detection of the real effect of treatments. As we consider the fact that various factors interact in the emergence of suicidal behavior, it is probable that drug effect may be regulated in the same way with the interactions among such factors. The fact that no treatment study manages to equally control the risk factors among treatment groups makes it hard to identify the causal factors in suicide-relevant cases. Furthermore, in the analysis of SSRIs, short-term risks alone were examined; hence it is a requirement to detect long-term risks and create futureoriented study designs with wider databases and closer monitoring procedures. There is a need for more research to develop a guideline/protocol exclusively for suicide prevention in patients with anxiety disorders.

### **8. Conclusion**

anxiety disorder cases, personality disorders exhibit quite a high prevalence as 35% in posttraumatic stress disorder, 47% in panic disorder with agoraphobia and generalized anxiety disorder, 48% in social phobia, and 52% in OCD. In anxiety disorder cases, the highest ratio (39%) was found in Group C personality disorders. Also in samplings with personality disorders, high ratio of anxiety was detected particularly among borderline personality disorder cases. It is agreed that borderline personality disorder is a high risk factor for recurrent suicidal behavior. Personality disorders comorbid with anxiety disorder display a number of clinical outcomes such as suicide risk and more severe and less treatable anxiety disorders, thereby clinicians should place particular emphasis on identifying potential personality disorders in patients with anxiety disorder. Further studies should focus on the causes and risk factors for suicidal behavior particularly in patients with anxiety disorders comorbid with

The basic principles of treatment of anxiety disorders in major depression involve longer treatment and higher doses than are usually required for major depression. The impact of psychosocial disability and severity of depressive symptoms can be ameliorated with appro‐ priate treatment. Screening for depressive symptoms as well as administering an appropriate therapy seems the best way to prevent suicide attempts [121]. Newer treatments, such as the combination of psychotherapy and pharmacotherapy, may prove to be of greatest benefit for individuals with comorbidity of anxiety disorders in psychiatric disorders [122]. For the recent 25 years, much progress has been made in the treatment of five specific anxiety disorders such as social phobia, obsessive-compulsive disorder, generalized anxiety disorder, and posttrau‐ matic stress disorder. Placebo-controlled evidences suggest that pharmacological and psy‐ chological treatments offer substantially effective solutions [21, 123]. Treatment of anxiety disorders involve antidepressants (selective serotonin reuptake inhibitors (SSRI) mostly) and cognitive behavioral therapy. Among patients diagnosed with mood disorder and comorbid anxiety disorders, it is advisable to administer higher doses of SSRI [124]. Besides, a long-term discussion has been going on about the use of SSRIs (paroxetine, fluoxetine, and citalopram) which, as some argue, may have a triggering/stipulating effect on adult suicides since 1991 and children since 2002. Apter et al. [125] stated that paroxetine taking adult patients with major depression are at higher risk for suicidal ideation and behavior, and the same authors also claimed that there was no attempt in OCD and social phobia cases. In sync with this finding, the benefits of sertraline outweigh its potential risks in suicidal behavior among OCD patients, and OCD's effects are, in contrast to its effects in major depression, further positive [126]. In younger patients diagnosed with major depression, the risk of suicidal behavior uncovered with treatment is even higher. It is suggested that the rise in suicidal ideation and attempt parallel to the use of antidepressants is more risky for children and teenagers [21, 123]. Rickels et al. [127] in their two randomized controlled studies reported the positive effects of long-released venlafaxine on GAD. Among children and teenagers major depression and in GAD patients with venlafaxine, there might be a stage between suicidal behaviors and

personality disorders.

118 A Fresh Look at Anxiety Disorders

**7. Treatment studies**

Traditionally, anxiety disorders have not been viewed as independent risk factors for suicidal behavior, and therefore assessment of anxiety disorders has not been particularly emphasized in clinical enquiries, and suicide screening tools specific anxiety disorders (e.g., generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder) may be independently associated with suicidality, to which they particularly contribute when they are comorbid with bipolar disorder, personality disorders, depression, schizophrenia, and substance use disor‐ ders. Despite methodological issues, these findings should prompt clinicians to evaluate more specifically the impact of anxiety disorders on suicidal behavior, particularly when they are comorbid. Further research into treatment of anxiety disorders in relation to preventing suicide is required.

### **Acknowledgements**

I offer thanks to our team for suggesting that we write a book about anxiety disorders and suicide.

### **Author details**

Cicek Hocaoglu\*

Address all correspondence to: cicekh@gmail.com

Recep Tayyip Erdogan University, Rize, Turkey

### **References**


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**Acknowledgements**

120 A Fresh Look at Anxiety Disorders

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128 A Fresh Look at Anxiety Disorders


### **Chapter 7**
