**Anxiety in Natural and Surgical Menopause — Physiologic and Therapeutic Bases**

Juan Francisco Rodríguez-Landa, Abraham Puga-Olguín, León Jesús Germán-Ponciano, Rosa-Isela García-Ríos and Cesar Soria-Fregozo

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60621

#### **Abstract**

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172 A Fresh Look at Anxiety Disorders

Generalized anxiety disorder is one of the most common psychiatric disorders, affecting a high percentage of human beings around the world. This emotional disorder possesses marked gender differences and occurs more often in women than in men, in a proportion of 2:1. Accompanying the reproductive cycle of women are significant fluctuations in plasma and brain steroid hormone concentrations, including oestradiol, progesterone, and allopregnanolone, among others. These hormonal changes are related to some illnesses and with the development of anxiety and mood swings occurring in the premenstrual and postpartum period, and particularly during the menopause. Menopause is a clinical term used to indicate the cessation of the woman's reproductive ability that occurs naturally, but also may be surgically induced by bilateral oophorectomy, with or without the removal of the Fallopian tubes and uterus. Natural menopause includes specific periods related to the physiological and hormonal changes produced by ovarian failure, it is usually a natural stage that occurs to women in midlife, during their late 40s or early 50s, indicating the end of the reproductive period in the woman. During the menopause transition years, women experience changes in the production of ovarian hormones, which are associated with significant changes in the physiological, emotional, and affective processes. Unfortunately, surgical menopause occurs at an early age, and produces similar physiological and psychiatric disorders, but they are more severe in this instance. In both cases, typical symptoms associated with menopause critically

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deteriorate the mental health of the women. In this way, the therapeutic management of clinical symptoms of menopause include replacement hormone therapy, the use of anxiolytic and antidepressant drugs, and other natural alternatives based on the use of chemical compounds obtained from plants such as soya. However, a general effective treatment for menopause symptoms does not yet exist. For this reason, experimental studies have proposed ovariectomy in rats as a potential tool to study the effects of a long-term absence of ovarian hormones associated with surgical menopause, which also allowed the study of substances with potential therapeutic application to ameliorate typical symptoms associated with surgical menopause. The aim of this chapter is to review the participation of ovarian hormones in the regulation of emotional and affective disorders in women with natural or surgical menopause; particularly their anatomical pathways, neurotransmission systems, and the resulting behavioural patterns. Finally, preclinical and clinical research suggested that longterm absence of ovarian hormones associated with natural or surgical menopause is the principal cause of physiological and psychiatric disorder in the women; therefore, oestrogenic compounds seem to play an important role in the maintenance of the brain structures that regulate anxiety, mood, memory, and cognitive functions in meno‐ pausal women.

**Keywords:** Anxiety, natural menopause, surgical menopause, oestrogens, experi‐ mental model, ovariectomy

### **1. Introduction**

Generalized anxiety disorder is one of the most common psychiatric disorders, affecting a high percentage of the general population around the world. This psychopathology possesses marked gender differences and occurs more often in women than in men [1]. During the reproductive cycle of women, fluctuations occur in plasma and brain steroid hormone concentrations, including oestradiol, progesterone, and allopregnanolone: a reduced metab‐ olite of progesterone. These hormonal changes are related to some illnesses and the develop‐ ment of anxiety and mood swings [2].

Low concentrations of steroid hormones are associated with irritability, anxiety, or depressive symptoms, and occur during the premenstrual, post-partum, and climacteric or post-meno‐ pausal periods. In particular, natural or surgical post-menopause is mainly characterized by a reduction of both oestradiol and progesterone because of failing ovarian function. These hormonal changes are associated with a major incidence of vasomotor symptoms, vaginal dryness, osteoporosis, cognitive deterioration, and hot flashes accompanied by perspiration, palpitations, irritability, anxiety, and mood swings. Unfortunately, emotional and affective alterations associated with the long-term absence of ovarian hormones are more severe in women who have undergone surgical menopause than women who experienced natural menopause. Disturbingly, surgical menopause is occurring more frequently in young women, in an economically productive stage, which impacts on the economy, on their quality of life, and, unfortunately, on their mental health [3].

Treatment of anxiety and depressive symptoms associated with the long-term absence of ovarian hormones produced by natural or surgical menopause, includes the use of benzodia‐ zepines (i.e., diazepam), some selective serotonin reuptake inhibitors (i.e., fluoxetine or paroxetine), and hormone replacement therapy (i.e., oestrogens, or a combination of oestro‐ gens plus progestagens), among others. Hormone replacement therapy has been used to ameliorate physiological, behavioural, and emotional alterations in post-menopausal women; for example, to reduce bone loss, hot flashes, irritability, and mood swings [4, 5]. Nevertheless, hormone replacement therapy is associated with several side-effects limiting their long-term use in vulnerable women. In this way, some investigations focusing on finding new therapeutic alternatives have explored the effects of some vegetables such as soya that contains high concentrations of the phyto-oestrogens genistein, daidzein, glycitein, and their conjugate metabolites. In some reports, there is evidence that phyto-oestrogens produces physiological effects similar to that produced by endogenous oestrogens. Apparently, these effects occur through actions on the oestradiol receptor-β [6, 7], which has been involved in the anxiolyticlike effect of endogenous and synthetic oestrogens at the experimental level.

To study the effect of the long-term absence of ovarian hormones associated with surgical menopause in the women, ovariectomy in rats has been used at a preclinical level as a potential tool to explore alterations in diverse organs and systems [8]. A rat experiencing a long-term absence of ovarian hormones induced by ovariectomy is considered as an early model of surgical menopause, which has allowed studying changes in cardiovascular, reproductive, motor, and bone systems, as well as changes in the sensitivity of neurotransmitter receptors in the brain. These changes in the brain impact negatively on the behaviour of the rats, producing higher indicators of anxiety-like behaviour and despair [6, 9]. Such facts support the hypothesis that rats with a chronic absence of ovarian hormones induced by ovariectomy could help us to understand the anxiety and mood swings typical of women who have undergone surgical menopause, as well as to screen new substances that could ameliorate anxiety symptoms in this particular group of women.

The aim of this chapter is to review the participation of ovarian hormones in the regulation of emotional and affective disorders in women experiencing natural or surgical menopause, particularly their anatomical pathways, neurotransmission systems, and the resulting behav‐ ioural patterns. Additionally, the principal pharmacological therapies used to ameliorate physiological and psychological symptoms in natural and surgical menopause will be discussed.

### **2. Natural and surgical menopause**

deteriorate the mental health of the women. In this way, the therapeutic management of clinical symptoms of menopause include replacement hormone therapy, the use of anxiolytic and antidepressant drugs, and other natural alternatives based on the use of chemical compounds obtained from plants such as soya. However, a general effective treatment for menopause symptoms does not yet exist. For this reason, experimental studies have proposed ovariectomy in rats as a potential tool to study the effects of a long-term absence of ovarian hormones associated with surgical menopause, which also allowed the study of substances with potential therapeutic application to ameliorate typical symptoms associated with surgical menopause. The aim of this chapter is to review the participation of ovarian hormones in the regulation of emotional and affective disorders in women with natural or surgical menopause; particularly their anatomical pathways, neurotransmission systems, and the resulting behavioural patterns. Finally, preclinical and clinical research suggested that longterm absence of ovarian hormones associated with natural or surgical menopause is the principal cause of physiological and psychiatric disorder in the women; therefore, oestrogenic compounds seem to play an important role in the maintenance of the brain structures that regulate anxiety, mood, memory, and cognitive functions in meno‐

**Keywords:** Anxiety, natural menopause, surgical menopause, oestrogens, experi‐

Generalized anxiety disorder is one of the most common psychiatric disorders, affecting a high percentage of the general population around the world. This psychopathology possesses marked gender differences and occurs more often in women than in men [1]. During the reproductive cycle of women, fluctuations occur in plasma and brain steroid hormone concentrations, including oestradiol, progesterone, and allopregnanolone: a reduced metab‐ olite of progesterone. These hormonal changes are related to some illnesses and the develop‐

Low concentrations of steroid hormones are associated with irritability, anxiety, or depressive symptoms, and occur during the premenstrual, post-partum, and climacteric or post-meno‐ pausal periods. In particular, natural or surgical post-menopause is mainly characterized by a reduction of both oestradiol and progesterone because of failing ovarian function. These hormonal changes are associated with a major incidence of vasomotor symptoms, vaginal dryness, osteoporosis, cognitive deterioration, and hot flashes accompanied by perspiration, palpitations, irritability, anxiety, and mood swings. Unfortunately, emotional and affective alterations associated with the long-term absence of ovarian hormones are more severe in women who have undergone surgical menopause than women who experienced natural menopause. Disturbingly, surgical menopause is occurring more frequently in young women,

pausal women.

174 A Fresh Look at Anxiety Disorders

**1. Introduction**

mental model, ovariectomy

ment of anxiety and mood swings [2].

Menopause is a clinical term used to indicate the cessation of a woman's reproductive ability. It may occur naturally, but also may be surgically induced by bilateral oophorectomy (removal of ovaries), with or without removal of the Fallopian tubes (salpingo-oophorectomy), and uterus (hysterectomy). Natural menopause includes specific periods (Figure 1) related with the physiological and hormonal changes produced by ovarian failure (Table 1). Menopause is usually a natural stage that occurs to women in midlife, during their late 40s or early 50s, indicating the end of the reproductive period in the woman [2]. During the menopause transition years, the women experiment fluctuations in the production and release of ovarian hormones, which produces significant changes in the physiological and affective processes. Not every woman experiences bothersome levels of these effects; it varies greatly from person to person and also depends of their lifestyles. Most women experience that their menstrual periods are gradually becoming less frequent, and that the timing of the start of the flow is usually less predictable.

**Figure 1.** Scheme illustrating the different phases that characterized the end of the reproductive period in women, un‐ der natural conditions.

The beginning of menopause (the last period from natural causes) typically occurs in an age range between 40 and 61 years, [10] with an average age for the last period of 51 years [12]. The average age of natural menopause in the majority of women occurs at 51 years [11], however, in some countries (i.e., the Philippines and India), the median age of natural menopause occurs earlier, at 44 years. [13]. Nonetheless, the World Health Organization indicates that the menopause occurs at the average age of 45–55 years around the world.

During natural or surgical menopause there are significant reductions of ovarian hormones' concentrations, particularly oestradiol, progesterone, and their metabolites. This influences the beginning of menopausal symptoms, including bone density loss and vasomotor altera‐ tions, accompanied by irritability, anxiety, and depression in some cases [2, 6, 14, 15]. Natural menopause is caused by follicular atresia in which there are ovarian follicles that do not respond to gonadotrophynes; for this reason, the ovaries lose their function, ovulation ceases, and the reproductive period of the woman ends. In this state, the oestrogen concentrations are lowest, increasing the follicular stimulant hormone (FSH) and luteinizing hormone (LH) in a minor proportion [16].


**Table 1.** Terms associated with natural menopause

uterus (hysterectomy). Natural menopause includes specific periods (Figure 1) related with the physiological and hormonal changes produced by ovarian failure (Table 1). Menopause is usually a natural stage that occurs to women in midlife, during their late 40s or early 50s, indicating the end of the reproductive period in the woman [2]. During the menopause transition years, the women experiment fluctuations in the production and release of ovarian hormones, which produces significant changes in the physiological and affective processes. Not every woman experiences bothersome levels of these effects; it varies greatly from person to person and also depends of their lifestyles. Most women experience that their menstrual periods are gradually becoming less frequent, and that the timing of the start of the flow is

**Figure 1.** Scheme illustrating the different phases that characterized the end of the reproductive period in women, un‐

The beginning of menopause (the last period from natural causes) typically occurs in an age range between 40 and 61 years, [10] with an average age for the last period of 51 years [12]. The average age of natural menopause in the majority of women occurs at 51 years [11], however, in some countries (i.e., the Philippines and India), the median age of natural menopause occurs earlier, at 44 years. [13]. Nonetheless, the World Health Organization indicates that the menopause occurs at the average age of 45–55 years around the world.

During natural or surgical menopause there are significant reductions of ovarian hormones' concentrations, particularly oestradiol, progesterone, and their metabolites. This influences

usually less predictable.

176 A Fresh Look at Anxiety Disorders

der natural conditions.

On the other hand, surgical menopause is associated with sudden and complete reduction of oestradiol, progesterone, and testosterone plasma concentrations [17], which predisposes the appearance of physiological and psychiatric alterations, such as occur in natural menopause, but with greater intensity.

### **3. Anxiety disorders and mood swings associated with natural or surgical menopause in women**

Menopause is a stage of biological development of women that implies physiological, psychological, and social changes. During menopause, women are vulnerable to cognitive and physical impairment as well as psychiatric illnesses as anxiety and depression. Hot flushes; night sweating; skin dryness and mucosa; even vaginal dryness; sleep disorders; and cognitive and behavioural changes are symptoms that deteriorate a woman's quality of life [18]. Mild anxiety and stress vulnerability are common in premenopause; while anxiety, depression, and irritability are more intense during perimenopause [19]. Anxiety disorders tend to be more chronic compared to mood disorders (i.e., depression) in a woman suffering during the menopause [20]. It is noteworthy that emotional and affective disorders are more severe in cases of surgical menopause compared with natural menopause, apparently due to the drastic suppression of hormonal production and the psychosocial context of the surgery and related illness.

During natural menopause, ovarian hormones biosynthesis (i.e., oestrogens and androgens) becomes gradually reduced, while surgical menopause is characterized by a drastic hormonal suppression. This reduction of hormone concentrations influences the impairment in neuronal functioning responsible for a predisposition to develop anxiety disorders and changes in general mood, mostly in woman with records of psychiatric illness. Women who had experi‐ enced disorders such as premenstrual syndrome or dysphoric premenstrual syndrome in their life, experience menopause with a certain degree of liberty and comfort with respect to their sexuality; on the other hand, women with records of psychiatric disorders can experience emotional and affective disorders more severely [21].

It has been found that between the ages of 42 to 52 years, women with high levels of anxiety during premenopause continue to experience this during menopause. Premenopausal woman with low levels of anxiety can be more susceptible to increased levels of anxiety during and after menopause transition [22]. Consistent with that findings, Jafari et al., 2014 [23], found that post-menopausal women, between the ages of 45 and 55, have high levels of anxiety compared to premenopausal women between 35 and 45.

Some authors have suggested that transition to menopause is the stage with the most risk of developing or increasing the symptoms of anxiety. Anxiety disorders such as panic disorder, social phobia, or generalized anxiety do not vary with the different stages of menopause [24]. However, studies showed that during the perimenopause, anxiety symptoms are higher than symptoms in pre- and post-menopause. Approximately 74% of women undergoing natural menopause experience hot flushes [24], which are associated with the development of anxiety symptoms. It is still controversial if anxiety develops before or in consequence of the vascular symptoms (i.e., hot flushes and night sweating) that characterized menopause.

Respecting the severity of the symptoms associated with menopause, there exists a consider‐ able variation between samples. African-American women report similar symptoms of anxiety and panic attacks, but a higher degree of severity in vascular motor symptoms (i.e., hot flushes in the chest and head, palpitations, and sweating) when compared with Asiatic women [25]. This difference in symptoms has been associated with lifestyles and nutrition as well as particularities in metabolic activity and the disruption of some neurotransmission systems in the brain [26], but it is not yet clear if anxiety precedes vascular symptoms or vice versa. On the other hand, a close negative relation between the severity of anxiety and depression symptoms and quality of life has been reported. In this sense, post-menopausal women with a low quality of life showed a higher index of anxiety and symptoms of depression than premenopausal women with a good quality of life [23].

physical impairment as well as psychiatric illnesses as anxiety and depression. Hot flushes; night sweating; skin dryness and mucosa; even vaginal dryness; sleep disorders; and cognitive and behavioural changes are symptoms that deteriorate a woman's quality of life [18]. Mild anxiety and stress vulnerability are common in premenopause; while anxiety, depression, and irritability are more intense during perimenopause [19]. Anxiety disorders tend to be more chronic compared to mood disorders (i.e., depression) in a woman suffering during the menopause [20]. It is noteworthy that emotional and affective disorders are more severe in cases of surgical menopause compared with natural menopause, apparently due to the drastic suppression of hormonal production and the psychosocial context of the surgery and related

During natural menopause, ovarian hormones biosynthesis (i.e., oestrogens and androgens) becomes gradually reduced, while surgical menopause is characterized by a drastic hormonal suppression. This reduction of hormone concentrations influences the impairment in neuronal functioning responsible for a predisposition to develop anxiety disorders and changes in general mood, mostly in woman with records of psychiatric illness. Women who had experi‐ enced disorders such as premenstrual syndrome or dysphoric premenstrual syndrome in their life, experience menopause with a certain degree of liberty and comfort with respect to their sexuality; on the other hand, women with records of psychiatric disorders can experience

It has been found that between the ages of 42 to 52 years, women with high levels of anxiety during premenopause continue to experience this during menopause. Premenopausal woman with low levels of anxiety can be more susceptible to increased levels of anxiety during and after menopause transition [22]. Consistent with that findings, Jafari et al., 2014 [23], found that post-menopausal women, between the ages of 45 and 55, have high levels of anxiety

Some authors have suggested that transition to menopause is the stage with the most risk of developing or increasing the symptoms of anxiety. Anxiety disorders such as panic disorder, social phobia, or generalized anxiety do not vary with the different stages of menopause [24]. However, studies showed that during the perimenopause, anxiety symptoms are higher than symptoms in pre- and post-menopause. Approximately 74% of women undergoing natural menopause experience hot flushes [24], which are associated with the development of anxiety symptoms. It is still controversial if anxiety develops before or in consequence of the vascular

Respecting the severity of the symptoms associated with menopause, there exists a consider‐ able variation between samples. African-American women report similar symptoms of anxiety and panic attacks, but a higher degree of severity in vascular motor symptoms (i.e., hot flushes in the chest and head, palpitations, and sweating) when compared with Asiatic women [25]. This difference in symptoms has been associated with lifestyles and nutrition as well as particularities in metabolic activity and the disruption of some neurotransmission systems in the brain [26], but it is not yet clear if anxiety precedes vascular symptoms or vice versa. On the other hand, a close negative relation between the severity of anxiety and depression symptoms and quality of life has been reported. In this sense, post-menopausal women with

symptoms (i.e., hot flushes and night sweating) that characterized menopause.

emotional and affective disorders more severely [21].

compared to premenopausal women between 35 and 45.

illness.

178 A Fresh Look at Anxiety Disorders

Symptoms of anxiety, irritability, depression, bluntness, mnesic disease, impairment of general capacity, and sleep disorders are the most frequent motives in women with perimenopause to attend to medical consultation [18]. It is common that women that refer to psychological discomfort in medical consultation during the whole menopause span are also the women that show less self-esteem and a low personal satisfaction [23]. Additionally, there is a relation between hormone levels and psychological wellbeing in menopausal women. For example, depression seems to increase when hormonal fluctuations occur in perimenopause, possibly as result of a lack of regulation of oestrogens over serotonergic activity and other neurotrans‐ mission systems in the brain [21]. Variations in circulating levels of androgens are related to mood disorders in young post-menopausal women, establishing a direct relation between androgen concentrations and symptoms of anxiety and depression in post-menopause [27].

Panic disorder is one of the most common anxiety disorders during menopause; it can develop once menopause has been completely established. Such disorder is more frequent in women with evident physical symptoms during menopause. In three groups of women classified in different ages (i.e., 50 to 59, 60 to 69, and 70 to 79 years old), panic attacks were more frequent in women between 50 to 59 years old. This group probably experienced perimenopause with variations in ovarian hormones production, an increased vulnerability to psychological stress, and somatic symptoms that can be more intense, which can increase the probability of developing anxiety. Other factors include negative experiences in life, general physical impairment, and comorbidity with other illness [28]. For example, women from 51 to 83 years old experienced at least one episode of panic attacks during the six months previous to suffering from a cardiovascular disorder, with a prevalence of 10%. It seems that anxiety is a risk factor that increases morbidity and mortality associated to cardiovascular illness in postmenopausal women [29].

Obsessive-compulsive disorder (OCD) is a mental illness associated with different events in the reproductive life of a woman. There are reports of a 47% of incidence of OCD during menopause while this percentage decreases considerably in post-menopausal women to 9 %. Although there are studies about the relation of menopause and OCD, the data are contradic‐ tory [30]. One research on women suffering natural or surgical post-menopause measured prevalence and comorbidity of OCD, the prevalence of OCD was about 7.1% and the more common obsessions was cleanliness, while the most common compulsions were cleanliness/ washing. Comorbidity for the different disorders was 63.2 %, with comorbidity and general‐ ized anxiety being the most frequent [31].

In relation to panic disorder (PD), some studies have related PD with vascular disturbances in perimenopausal women that attended medical consultation, with a prevalence of 18%. However, this research did not specify how it determined menopause onset; it seems the researchers used only verbal reports of patients [32], so these results must be interpreted carefully.

Concerning surgical menopause, very little literature about anxiety attacks and this kind of menopause exists. One medical case reported that a woman with a surgical extirpation of ovarian developed physiological and psychological changes similar to those of natural menopause, but also immediately developed symptoms of severe anxiety that impaired her quality of life [33]. The emotional and affective symptoms associated with surgical menopause vary between individuals, but it has been reported that bilateral extirpation of ovaries before natural menopause is related to the development of anxiety disorders and the increase of cognitive impairment risk, compared with women that experience natural menopause [34].

In summary, reported data associating anxiety disorders to natural or surgical menopause are still contradictory, perhaps due to differences between the populations of study and the variations in criteria for measuring both menopause and anxiety. Some studies report that symptoms of anxiety increase during perimenopause and decrease later in post-menopause [35]. Other studies suggest that anxiety symptoms are not directly related to a particular stage of menopause [36]. For example, Freeman et al. (2005) [37] reported that previous medical records of depression and stress vulnerability are strong predictors of anxiety during meno‐ pause, while Moilanen et al. (2010) [36] only related the lifestyle (i.e., obesity, sedentary lifestyle, and alcohol consumption) with the predisposition to suffer anxiety episodes during natural menopause. Besides, most of the investigations do not offer solid data about prevalence of anxiety disorders that fulfil the diagnostic criteria. It seems that most of the few studies comparing natural and surgical menopause have found a relation between vascular alterations and symptoms of anxiety; however, this relationship is not definitive since it must be assured that somatic and psychological symptoms were not confused with anxiety symptoms in these studies' particular populations. At the time of writing, predisposal factors of emotional and affective alterations during natural or surgical menopause have not been clearly identified, but it seems evident that during menopausal stages there is an increased vulnerability to stress which increases the prevalence of anxiety and depression symptoms that impair quality of life during natural or surgical menopause. This makes necessary specific studies with standar‐ dized criteria for measuring the factors that produce these disorders in order to design therapeutic strategies, including pharmacological treatments that improve the quality of life of women suffering natural or surgical menopause.

### **4. Pharmacological treatment of anxiety disorders in menopausal women: Benefits versus side-effects**

Despite the evidence that in natural and surgical menopause there is a high incidence of anxiety and depression disorders, there are few controlled studies evaluating the efficacy of pharma‐ cological treatments in this particular population, while there is a worryingly high frequency of self-medication using anxiolytic drugs in menopausal women. Treatment selection for controlling the symptoms of menopausal women requires establishing a balance between the benefits on mood and the potential risks to health. It is very important to consider the clinical background of the patient; in cases of young women who have undergone surgical menopause at an early age (24 to 38 years old), efficiency of the pharmacological response can vary compared with women who experienced natural menopause.

Concerning surgical menopause, very little literature about anxiety attacks and this kind of menopause exists. One medical case reported that a woman with a surgical extirpation of ovarian developed physiological and psychological changes similar to those of natural menopause, but also immediately developed symptoms of severe anxiety that impaired her quality of life [33]. The emotional and affective symptoms associated with surgical menopause vary between individuals, but it has been reported that bilateral extirpation of ovaries before natural menopause is related to the development of anxiety disorders and the increase of cognitive impairment risk, compared with women that experience natural menopause [34].

In summary, reported data associating anxiety disorders to natural or surgical menopause are still contradictory, perhaps due to differences between the populations of study and the variations in criteria for measuring both menopause and anxiety. Some studies report that symptoms of anxiety increase during perimenopause and decrease later in post-menopause [35]. Other studies suggest that anxiety symptoms are not directly related to a particular stage of menopause [36]. For example, Freeman et al. (2005) [37] reported that previous medical records of depression and stress vulnerability are strong predictors of anxiety during meno‐ pause, while Moilanen et al. (2010) [36] only related the lifestyle (i.e., obesity, sedentary lifestyle, and alcohol consumption) with the predisposition to suffer anxiety episodes during natural menopause. Besides, most of the investigations do not offer solid data about prevalence of anxiety disorders that fulfil the diagnostic criteria. It seems that most of the few studies comparing natural and surgical menopause have found a relation between vascular alterations and symptoms of anxiety; however, this relationship is not definitive since it must be assured that somatic and psychological symptoms were not confused with anxiety symptoms in these studies' particular populations. At the time of writing, predisposal factors of emotional and affective alterations during natural or surgical menopause have not been clearly identified, but it seems evident that during menopausal stages there is an increased vulnerability to stress which increases the prevalence of anxiety and depression symptoms that impair quality of life during natural or surgical menopause. This makes necessary specific studies with standar‐ dized criteria for measuring the factors that produce these disorders in order to design therapeutic strategies, including pharmacological treatments that improve the quality of life

**4. Pharmacological treatment of anxiety disorders in menopausal women:**

Despite the evidence that in natural and surgical menopause there is a high incidence of anxiety and depression disorders, there are few controlled studies evaluating the efficacy of pharma‐ cological treatments in this particular population, while there is a worryingly high frequency of self-medication using anxiolytic drugs in menopausal women. Treatment selection for controlling the symptoms of menopausal women requires establishing a balance between the benefits on mood and the potential risks to health. It is very important to consider the clinical background of the patient; in cases of young women who have undergone surgical menopause

of women suffering natural or surgical menopause.

**Benefits versus side-effects**

180 A Fresh Look at Anxiety Disorders

The therapeutic treatment for the control of symptoms of anxiety includes hormonal replace‐ ment therapy, antidepressant with anxiolytic activity, and some therapies based on the use of chemical compounds isolated from vegetables (i.e., soya), which have shown certain anxiolytic potential (Table 2).




**Table 2.** Pharmacological treatment of anxiety disorders in menopausal women.

### **5. Hormonal replacement therapy**

**Type of Therapy**

182 A Fresh Look at Anxiety Disorders

Conjugated equine estrogen (Premarin)

Dehydroepiandroste rone (DHEA)

Testosterone (gel hidroalcoholyc TESTOGEL®)

**Antidepressant** Venlafaxine

**Phytoestrogens** Red clover extracts (MF11RCE,

**Condition**

Hysterectomy and bilateral oophorectomy

Hysterectomy and bilateral oophorectomy

Total abdominal hysterectomy/ bilateral salpingo-oophorectomy

(48-51 year)

(48-51 year)

Natural menopause (50-65 year)

12 month of amenorrea

>12 month of amenorrea

(45-55 year)

Paroxetine Natural menopause (62 year)

(40 year)

Total abdominal hysterectomy/ bilateral salpingo-oophorectomy

(48 year)

(50 year)

**(Average age) Dosage Therapeutic**

(2 mg/day; v.o.

(50 mg/day;

(0.625 mg/day;

(25 mg/day; v.o.;

(50 mg/day; t.d.;

(450 mg/day;

10 mg/day; 1 week and the subsequent dose of 20 mg/day; 6 months.

(80 mg/day; v.o.;

3 month) Anxiolytic

v.o.; 6 month) Anxiolytic

Anxiolytic

v.o.; 12 month) Anxiolytic

**effects**

**Side-effects Reference**

[46]

[46]

[88]

[54]

[89]

cerebrovascular accidents and myocardial infarction

(Welty, 2003).

Increased risk of myocardial infarction, breast cancer and strokes, besides headache and nausea (Gupta et al.,

; 6 month) Anxiolytic [43]

t.d.; 12 month) Anxiolytic [87]

2013).

2003).

al., 2006).

Headache, weight gain, facial hair, increased appetite (Nathorst-Böös et

Dry mouth, altered appetite, abdominal discomfort, decreased libido, insomnia, headache and nausea (Hickey et al., 2005; Iglesias et al., 2009; Handley et al., 2015).

Decreased libido, insomnia, headache and nausea (Hickey et al., 2005; Handley et al.,

2015).

3 month) Anxiolytic Without effects. [38]

12 month) Anxiolytic Acne and hair loss (Welty,

Reduced oestrogen concentrations during menopause impacts different biological systems, including the central nervous system. The psychiatric disorders most common during menopause include loss of motivation, lack of mental concentration, irritability, aggression, mood swings, mental tension, anxiety, and depression disorders. Anxiety in particular occurs mainly in women who have been susceptible to suffering anxiety during their whole life. It is well known that exogenous administration of oestrogens or progesterone not only prevents the common symptoms of menopause [5], but is also able to improve the mood and emotional state, and reduce the symptoms of anxiety [38, 39]. In this sense, the use of oestrogens to treat anxiety is preferable to the use of psychopharmacological drugs.

Rocca and collaborators (2008) [34] reported that women who experience surgical menopause at an early age are not responsive to the treatment with oestrogens for symptoms of generalized anxiety, while women suffering during a natural menopause but who experienced surgical extirpation of the ovaries were sensitive to treatment with ethinyl oestradiol (3.9 mg/week) which significantly decreased the symptoms of anxiety [40, 41]. This finding suggests that physiological and neurochemical conditions associated with the reduction of hormonal levels in natural and surgical menopause are age-dependent, and impacts on the establishment of anxiolytic effects of oestrogenic therapy.

Clinical studies agree that chronic administration of 17β-oestradiol to women with natural [42] or surgical menopause [43] is effective in reducing symptoms of anxiety. However, some studies relate the use of 17β-oestradiol with an increase in the risk of developing venous thromboembolism [44], strokes, and myocardial infarction in women both with and without a family history of this illness; apparently, the use of a transdermal patch with oestrogens minimizes the secondary effects but unfortunately also minimizes therapeutic effects [45].

Therapy with equine conjugate oestrogens at a dose of 0.625 mg/day also produces significant anxiolytic effects, in the same way that 25 mg/day of dehydroepiandrosterone (DHEA) does; both treatments significantly reduce genitourinary, vasomotor, psychological, vaginal dryness symptoms, and improve libido [46]. Unfortunately, the use of oestrogens alone or in combi‐ nation with medroxyprogesterone acetate (synthetic progestin) used to ameliorate the symptoms associated with the menopause, also has side-effects and increases the risk of heart attacks, breast cancer, and strokes. Other symptoms include headaches, nausea, and (in the case of DHEA) secondary effects of an androgenic kind such as acne and hair loss [45, 46].

On the other hand, there are different alternative drugs for oestrogenic therapy when it is contraindicated, for example gonadomimetics such as Tibolone. This drug is a synthetic steroid from which three metabolites are produced: 3 alpha-OH-tibolone, 3 beta-tibolone with oestrogenic activity, and the isomer tibolone, which exerts a weak influence on progestegenic and androgenic activity. Tibolone, 2.5 mg/day, reduces the symptoms of generalized anxiety in menopausal women, who had undergone a hysterectomy or bilateral oophorectomy [41, 43] and in women experiencing a natural menopause [42]. It seems that these anxiolytic effects could be associated with an increase of β–endorphin concentrations in blood and the pituitary gland [47].

Collateral effects of the oestrogenic therapy include vaginal bleeding in women that still have a uterus, which in some cases determines the use of Tibolone [48], given that it not only produces anxiolytic effects but also reduce symptoms at vegetative and cardiovascular levels. Additionally, it also reduces triglyceride, total cholesterol, and bad cholesterol (LDL) levels, while increasing good cholesterol (HDL) levels, reduces loss of bone density, and increases libido in post-menopausal women [46]. Data available about the chronic use of Tibolone show that it can reduce the risk of bone fractures, and breast and colon cancers, but also increases the risk of strokes in women older than 60 [49].

Hormonal replacement therapy, in general, is contraindicated in women with hepatic and cardiovascular illness, and with records of thrombovascular or cerebrovascular disease, as well as breast and cervical cancer. Nevertheless, it exists as a treatment option with excellent clinical results.

### **6. Antidepressants**

Women suffering during the menopause have reduced serotonergic activity associated with low concentrations of steroid hormones, which is associated with the symptoms of anxiety and depression [50]. The reduction in oestrogenic levels during menopause could alter the availability of cerebral tryptophan used in serotonin synthesis, allowing the establishment of psychological symptoms typical of menopause. In consequence, the use of Selective Serotonin Reuptake Inhibitors (SSRI) can control the symptoms of anxiety and depression in menopausal women [50].

The use of SSRI to control symptoms of anxiety and depression in menopausal women includes mainly paroxetine, fluoxetine, sertraline, citalopram, and venlafaxine, which are also used to control vascular symptoms, and mainly hot flushes. Usage of these drugs has an appropriate tolerance and security window, with the exception of some adverse effects including the reduction of libido, insomnia, headache, and nausea [51, 52].

Venlafaxine is used for treatment of anxiety disorders most common in menopause, such as generalized anxiety, panic attacks, and social phobia. Very few studies evaluate the effects of antidepressants in women experiencing menopause and diagnosed with some anxiety disorder, due to the fact that frequently symptoms of anxiety can be confused with emotional disturbances characteristic of menopause, such as palpitations, irritability, and sweating [53].

One study by Iglesias et al. (2009) [54] including women between 45 to 55 years old experi‐ encing natural menopause, showed the anxiolytic effect of venlafaxine (450 mg/day/six months). Despite the use of relatively high doses compared to the standard dose (150 mg/day), no potentially dangerous secondary effects were reported, with the exceptions of mouth dryness, appetite changes, abdominal discomfort, headaches, and, in some cases, sexual dysfunction.

### **7. Alternative therapies**

nation with medroxyprogesterone acetate (synthetic progestin) used to ameliorate the symptoms associated with the menopause, also has side-effects and increases the risk of heart attacks, breast cancer, and strokes. Other symptoms include headaches, nausea, and (in the case of DHEA) secondary effects of an androgenic kind such as acne and hair loss [45, 46].

On the other hand, there are different alternative drugs for oestrogenic therapy when it is contraindicated, for example gonadomimetics such as Tibolone. This drug is a synthetic steroid from which three metabolites are produced: 3 alpha-OH-tibolone, 3 beta-tibolone with oestrogenic activity, and the isomer tibolone, which exerts a weak influence on progestegenic and androgenic activity. Tibolone, 2.5 mg/day, reduces the symptoms of generalized anxiety in menopausal women, who had undergone a hysterectomy or bilateral oophorectomy [41, 43] and in women experiencing a natural menopause [42]. It seems that these anxiolytic effects could be associated with an increase of β–endorphin concentrations in blood and the pituitary

Collateral effects of the oestrogenic therapy include vaginal bleeding in women that still have a uterus, which in some cases determines the use of Tibolone [48], given that it not only produces anxiolytic effects but also reduce symptoms at vegetative and cardiovascular levels. Additionally, it also reduces triglyceride, total cholesterol, and bad cholesterol (LDL) levels, while increasing good cholesterol (HDL) levels, reduces loss of bone density, and increases libido in post-menopausal women [46]. Data available about the chronic use of Tibolone show that it can reduce the risk of bone fractures, and breast and colon cancers, but also increases

Hormonal replacement therapy, in general, is contraindicated in women with hepatic and cardiovascular illness, and with records of thrombovascular or cerebrovascular disease, as well as breast and cervical cancer. Nevertheless, it exists as a treatment option with excellent clinical

Women suffering during the menopause have reduced serotonergic activity associated with low concentrations of steroid hormones, which is associated with the symptoms of anxiety and depression [50]. The reduction in oestrogenic levels during menopause could alter the availability of cerebral tryptophan used in serotonin synthesis, allowing the establishment of psychological symptoms typical of menopause. In consequence, the use of Selective Serotonin Reuptake Inhibitors (SSRI) can control the symptoms of anxiety and depression in menopausal

The use of SSRI to control symptoms of anxiety and depression in menopausal women includes mainly paroxetine, fluoxetine, sertraline, citalopram, and venlafaxine, which are also used to control vascular symptoms, and mainly hot flushes. Usage of these drugs has an appropriate tolerance and security window, with the exception of some adverse effects including the

reduction of libido, insomnia, headache, and nausea [51, 52].

gland [47].

184 A Fresh Look at Anxiety Disorders

results.

women [50].

**6. Antidepressants**

the risk of strokes in women older than 60 [49].

The collateral effects produced by hormone replacement therapy and the lack of controlled studies evaluating the therapeutic effect of antidepressants in women suffering menopause have encouraged research into new alternative therapies that control the symptoms charac‐ teristic of menopause but which few or no undesirable side-effects. At the time of writing, the use of chemical compounds obtained from plants (i.e., phyto-oestrogens) has been evaluated as a potential therapeutic option due to the oestrogenic activity over β-oestrogen receptors in the osseous system, reproductive system, and central nervous system [55, 56]. Although phytooestrogens seem to be less potent than conventional oestrogens [57] some preclinical and clinical studies support its potential use in therapeutic treatment of osteoporosis, vascular disorders, and the symptoms of anxiety and depression [38].

Some clinical studies have reported that isoflavones are effective in improving classical menopause symptoms, including those related to anxiety and mood swings. The phytooestrogens from magnolia bark extract significantly reduces the relevant psycho-affective symptoms, particularly anxiety, irritability, and insomnia in menopausal women, with a scarcity of side-effects [58].

In women experiencing natural menopause, the therapeutic effect of isoflavones synthetized from extracts of red clover (*Trifolium pratense*) was studied. The administration of 80 mg/day of isoflavones during three months (MF11RCE capsule with 40 mg of isoflavones biochanin A, formonometin, genistein, and daidzein) in women experiencing natural menopause reduced the symptoms of generalized anxiety 76% measured by the Hospital Anxiety and Depression Scale (HADS) and compared with basal measures, while with the Zung's Self Rating Depression Scale there was a reduction of 80.6% of symptoms with respect to basal [38]. It is noteworthy to point out that women who received a placebo also significantly reduced the symptoms of anxiety, but only 21.7% with respect to basal. These authors suggest that isoflavones isolated from red clover are efficient in treating the symptoms of anxiety and depression in women experiencing menopause.

On the other hand, Albert et al. (2001) [59], in a multicentric, open, prospective, observational, and nonrandomized clinical trial involving 190 post-menopausal women, tested the effect of a preparation rich in isoflavones (PHYTO SOYA, capsules containing 17.5 mg isoflavones) on symptomatology derived from the lack of oestrogens (i.e., hot flushes, sleep disorder, anxiety, depression, vaginal dryness, loss of libido, and bone pain). Each patient received 35 mg of isoflavones per day in two doses, during four months of treatment. In this study, most of the women reported a statistically significant decrease in all evaluated parameters, including a significant reduction of symptomatology of anxiety and depression, without severe sideeffects and with excellent tolerance. Nonetheless, more data from a double-blind, randomized study performed with 50 women (with an average age of 53.3 ± 3.1 years) with menopausal symptoms, the administration of the phyto-oestrogens genistein and daidzein during three months produced significant reductions in hot flushes only, but not in anxiety, insomnia, or vaginal dryness [60]. In this way, diverse studies of menopausal women have reported a particular effectiveness of phyto-oestrogens in the control of vasomotor symptoms, principally in the control of hot flushes [61–63], but few have demonstrated effectiveness in the control of anxiety and depressive symptoms [38, 58, 59]. There are in fact few studies that explore the clinical relevance of phyto-oestrogens in the control of emotional and affective disorders in menopausal women, which limit the wide use of these substances in the treatment of anxiety and depressive disorders. Considering the controversy of the effectiveness of phyto-oestro‐ gens in the management of physiological and psychiatric disorders associated with the menopause, additional studies are needed to further address the complex array of factors that may affect efficacy, such as dose, isoflavone structure, baseline of typical symptoms in the menopause, and treatment duration [61]. Only then will it be possible to consider phytooestrogens as a safe and efficacious alternative for treating symptoms associated with meno‐ pause and to remove the present barrier to recommending its use for treatment.

### **8. Ovariectomized rats as an animal model for surgical menopause**

Surgical menopause in women is produced by ablation of the ovaries (oophorectomy) with or without the uterus, which produces a similar symptomatology to that observed in natural menopause, but with an increase in intensity. In this way, bilateral ovariectomy in rats has been proposed as a tool to reproduce physiological and emotional alterations related with the reduction of ovarian hormones (Table 3), as occurring in women subjected to surgical meno‐ pause; in other words, that surgical manipulation of rats is proposed as an experimental model to study emotional and physiological changes that occur in women [8].

Some experimental studies of ovariectomized rats show a body-weight gain [64] and reduction of bone density as in osteoporosis [65], similar to that identified in menopausal women as a consequence of the long-term absence of ovarian hormones, in particular oestradiol, proges‐ terone, and their reduced metabolites [65]. In this state, other physiological alterations that produce atrophy of the skin and mucosa also occur [66], such as hair loss, deterioration of attention and concentration capacity, reduced memory capacity, and loss of libido [67, 68]. The absence of oestrogens disrupts the immune, motor [69], and cardiovascular systems [70]; in


**Table 3.** Cerebral and anxiety-like behavior changes associated with ovariectomy in the rat.

On the other hand, Albert et al. (2001) [59], in a multicentric, open, prospective, observational, and nonrandomized clinical trial involving 190 post-menopausal women, tested the effect of a preparation rich in isoflavones (PHYTO SOYA, capsules containing 17.5 mg isoflavones) on symptomatology derived from the lack of oestrogens (i.e., hot flushes, sleep disorder, anxiety, depression, vaginal dryness, loss of libido, and bone pain). Each patient received 35 mg of isoflavones per day in two doses, during four months of treatment. In this study, most of the women reported a statistically significant decrease in all evaluated parameters, including a significant reduction of symptomatology of anxiety and depression, without severe sideeffects and with excellent tolerance. Nonetheless, more data from a double-blind, randomized study performed with 50 women (with an average age of 53.3 ± 3.1 years) with menopausal symptoms, the administration of the phyto-oestrogens genistein and daidzein during three months produced significant reductions in hot flushes only, but not in anxiety, insomnia, or vaginal dryness [60]. In this way, diverse studies of menopausal women have reported a particular effectiveness of phyto-oestrogens in the control of vasomotor symptoms, principally in the control of hot flushes [61–63], but few have demonstrated effectiveness in the control of anxiety and depressive symptoms [38, 58, 59]. There are in fact few studies that explore the clinical relevance of phyto-oestrogens in the control of emotional and affective disorders in menopausal women, which limit the wide use of these substances in the treatment of anxiety and depressive disorders. Considering the controversy of the effectiveness of phyto-oestro‐ gens in the management of physiological and psychiatric disorders associated with the menopause, additional studies are needed to further address the complex array of factors that may affect efficacy, such as dose, isoflavone structure, baseline of typical symptoms in the menopause, and treatment duration [61]. Only then will it be possible to consider phytooestrogens as a safe and efficacious alternative for treating symptoms associated with meno‐

186 A Fresh Look at Anxiety Disorders

pause and to remove the present barrier to recommending its use for treatment.

to study emotional and physiological changes that occur in women [8].

**8. Ovariectomized rats as an animal model for surgical menopause**

Surgical menopause in women is produced by ablation of the ovaries (oophorectomy) with or without the uterus, which produces a similar symptomatology to that observed in natural menopause, but with an increase in intensity. In this way, bilateral ovariectomy in rats has been proposed as a tool to reproduce physiological and emotional alterations related with the reduction of ovarian hormones (Table 3), as occurring in women subjected to surgical meno‐ pause; in other words, that surgical manipulation of rats is proposed as an experimental model

Some experimental studies of ovariectomized rats show a body-weight gain [64] and reduction of bone density as in osteoporosis [65], similar to that identified in menopausal women as a consequence of the long-term absence of ovarian hormones, in particular oestradiol, proges‐ terone, and their reduced metabolites [65]. In this state, other physiological alterations that produce atrophy of the skin and mucosa also occur [66], such as hair loss, deterioration of attention and concentration capacity, reduced memory capacity, and loss of libido [67, 68]. The absence of oestrogens disrupts the immune, motor [69], and cardiovascular systems [70]; in

addition, an increase in emotional (i.e., anxiety) and affective (i.e., depression) alterations that negatively impact on women's quality of life also occurs. It has been suggested that these alterations are related to the long-term absence of ovarian hormones, which play an important role in the regulation of diverse physiological processes in gastrointestinal [71], metabolic, and bone [64, 65] systems, as well as in the regulation of emotional and affective states. All those alterations of the different systems are produced at the experimental level through the ablation of the ovaries in the rat; therefore this surgical manipulation has been considered as an appropriate model to study medical alterations occurring in women undergoing surgical menopause [6, 8, 58, 62].

In rats, the long-term absence of ovarian hormones produced by ovariectomy reduces GABAergic neurotransmission in diverse brain structures [72]. It also produces a reduced sensitivity of the GABAA, possibly associated with a reduced expression of mRNA of α2 and α3 subunits of this receptor [73]. As mentioned above, this is important because the GABAA receptor is the action site of clinically effective anxiolytic drugs such as benzodiazepines; those molecular modifications in the GABAA receptor could explain the reduced effectiveness of anxiolytic pharmacological therapies in menopausal women.

On the other hand, ovariectomies performed on rats reduce the density of oestrogen receptor α and β in the hippocampus [74]; in addition, reduced activity of glutamate receptors in the basolateral amygdala also occurs [75], and these neurochemical changes are accompanied by an increase in anxiety-like behaviour. While administration of an agonist of the glutamate receptors produces an anxiolytic-like effect in the ovariectomized rats, it is dependent on the availability of oestrogens in the basolateral amygdala [75].

Likewise, the ovariectomy of rats reduces the monoaminergic neurotransmission affecting the production and release of norepinephrine, dopamine, and serotonin in the brain [76]. It has been proposed that reduced monoaminergic neurotransmission in the hippocampus and accumbens nucleus could be related to the presence of anxiety-like behaviour, while admin‐ istration of oestrogenic compounds in ovariectomized rats produces anxiolytic-like effects [77], possibly associated with the reactivation of brain neurotransmission. Some investigations indicate that the lower concentration of oestrogens in the brain associated with ovariectomy reduces the activity of the enzyme tryptophan hydroxylase-2, which reduces the availability of serotonin and their transportation in the dorsal raphe nucleus [78]. Administration of oestrogenic compounds in ovariectomized rats, on the other hand, produces anxiolytic-like effects [79].

The rats with a long-term absence of ovarian hormones produced by ovariectomy are more vulnerable to environmental stressors. In this case, rats with long-term ovariectomies subjected to chronic mild stress show more anxiety-like behaviour than rats with short-term ovariectomy in the elevated plus-maze, indicating that the frame time in the absence of ovarian hormones plays an important role in response to stress. Vulnerability to stress in ovariectomized rats is associated with a reduced cellular proliferation in the dentate gyrus [79], and reduced density of dendritic spines in CA1 pyramidal neurons [80]. These neuroanatomical changes at brain level are proposed as part of the neurobiological substrate of the altered stress response and higher predisposition to develop emotional (i.e., anxiety) and affective (i.e., depression) disorders [67] in women experiencing both a natural or a surgical menopause.

In rats with the long-term absence of ovarian hormones induced by ovariectomy, it has been possible to study the same emotional and affective changes as occur in women as a result of surgical menopause. Rats with 12 post-ovariectomy weeks show higher anxiety-like behaviour than rats with three post-ovariectomy weeks [8]. Interestingly, this anxiety-like behaviour is reduced with anxiolytic drugs (i.e., diazepam), some natural chemical compounds (i.e., isoflavones), or some extract of plant (*Montanoa tomentosa*). In rats with long-term absence of ovarian hormones produced by ovariectomy, the effect of several doses of isoflavone genistein (0.25, 0.5, and 1.0 mg/kg) during four consecutive days was explored. This treatment schedule produces an increase in the time spent in exploration of an illuminated compartment and the number of explorations towards this compartment in the light/dark test: a validated model to screen drugs with a potential anxiolytic effect. These changes in rat behaviour are an indicator of a reduced anxiety-like behaviour, such as occur in this experimental model when anxiolytic drugs like diazepam are evaluated [6]. Interestingly, the anxiolytic-like effect produced by the isoflavone genistein is antagonized by tamoxifen, a non-selective antagonist of the β-oestradiol receptors [7]. The aforementioned facts support the idea that isoflavones activate the βoestrogen receptor which play a important role in the anxiolytic effects produced by natural oestradiol and other oestrogenic synthetic compounds [81]. In this way, these data support the hypothesis that phyto-oestrogen could be a possible therapeutic alternative in the natural management of anxiety disorders in menopausal women. In support, clinical studies have shown that administration of 34–100 mg/day of isoflavones from soya reduces the typical symptomatology of menopausal women: principally, vasomotor problems [82]. In other studies, the administration of isoflavones to menopausal women also reduces symptoms of anxiety and depression disorders [38, 58, 83].

In an early study, the effect of an aqueous extract of *Montanoa tomentosa* in rats with a longterm absence of ovarian hormones was evaluated [84]. In this study, the acute administration of the extract produced a significant reduction of anxiety-like behaviour when rats were evaluated in the elevated plus maze. These findings are interesting because the traditional use of this plant extract had been recommended in the ancient traditional medicine from México, as it was described in the *Badianus Codex* or *Libellus de Medicinalibus Indorum Herbis* (1552). It supports the potential use of this extract in the future as a natural alternative to ameliorate anxiety symptoms related with changes in ovarian hormones [84, 85].

In short, the aforementioned data indicate that ovariectomy in rats produces long-term behavioural and physiological changes that mimic the symptoms that occur in women who have undergone surgical menopause, and permit the exploration of possible therapeutic alternatives at an experimental level to ameliorate emotional and affective disorders associated with the long-term absence of ovarian hormones.

### **9. Conclusion**

In rats, the long-term absence of ovarian hormones produced by ovariectomy reduces GABAergic neurotransmission in diverse brain structures [72]. It also produces a reduced sensitivity of the GABAA, possibly associated with a reduced expression of mRNA of α2 and α3 subunits of this receptor [73]. As mentioned above, this is important because the GABAA receptor is the action site of clinically effective anxiolytic drugs such as benzodiazepines; those molecular modifications in the GABAA receptor could explain the reduced effectiveness of

On the other hand, ovariectomies performed on rats reduce the density of oestrogen receptor α and β in the hippocampus [74]; in addition, reduced activity of glutamate receptors in the basolateral amygdala also occurs [75], and these neurochemical changes are accompanied by an increase in anxiety-like behaviour. While administration of an agonist of the glutamate receptors produces an anxiolytic-like effect in the ovariectomized rats, it is dependent on the

Likewise, the ovariectomy of rats reduces the monoaminergic neurotransmission affecting the production and release of norepinephrine, dopamine, and serotonin in the brain [76]. It has been proposed that reduced monoaminergic neurotransmission in the hippocampus and accumbens nucleus could be related to the presence of anxiety-like behaviour, while admin‐ istration of oestrogenic compounds in ovariectomized rats produces anxiolytic-like effects [77], possibly associated with the reactivation of brain neurotransmission. Some investigations indicate that the lower concentration of oestrogens in the brain associated with ovariectomy reduces the activity of the enzyme tryptophan hydroxylase-2, which reduces the availability of serotonin and their transportation in the dorsal raphe nucleus [78]. Administration of oestrogenic compounds in ovariectomized rats, on the other hand, produces anxiolytic-like

The rats with a long-term absence of ovarian hormones produced by ovariectomy are more vulnerable to environmental stressors. In this case, rats with long-term ovariectomies subjected to chronic mild stress show more anxiety-like behaviour than rats with short-term ovariectomy in the elevated plus-maze, indicating that the frame time in the absence of ovarian hormones plays an important role in response to stress. Vulnerability to stress in ovariectomized rats is associated with a reduced cellular proliferation in the dentate gyrus [79], and reduced density of dendritic spines in CA1 pyramidal neurons [80]. These neuroanatomical changes at brain level are proposed as part of the neurobiological substrate of the altered stress response and higher predisposition to develop emotional (i.e., anxiety) and affective (i.e., depression)

In rats with the long-term absence of ovarian hormones induced by ovariectomy, it has been possible to study the same emotional and affective changes as occur in women as a result of surgical menopause. Rats with 12 post-ovariectomy weeks show higher anxiety-like behaviour than rats with three post-ovariectomy weeks [8]. Interestingly, this anxiety-like behaviour is reduced with anxiolytic drugs (i.e., diazepam), some natural chemical compounds (i.e., isoflavones), or some extract of plant (*Montanoa tomentosa*). In rats with long-term absence of ovarian hormones produced by ovariectomy, the effect of several doses of isoflavone genistein (0.25, 0.5, and 1.0 mg/kg) during four consecutive days was explored. This treatment schedule

disorders [67] in women experiencing both a natural or a surgical menopause.

anxiolytic pharmacological therapies in menopausal women.

availability of oestrogens in the basolateral amygdala [75].

effects [79].

188 A Fresh Look at Anxiety Disorders

Anxiety disorders are strongly associated with natural and surgical menopause, principally due to the prolonged absence of oestrogen concentration levels in plasma and the brain. Anxiety is related to hot flashes in most of clinical studies. Finally, preclinical and clinical research suggested that the long-term absence of ovarian hormones associated with natural or surgical menopause is the principal cause of physiological and psychiatric disorder in the women; therefore, oestrogenic compounds seem to play a important role in the maintenance of the brain structures that regulate anxiety, mood, memory, and cognitive functions in menopausal women. Despite advances in the development of diverse therapeutic schedules to ameliorate typical physiological and psychiatric symptoms associated with natural or surgical menopause, we still lack of an efficient treatment to ameliorate symptoms of meno‐ pause. The actual therapeutic schedules are partially effective, but they produce some sideeffects that limit their use in sensitive women. In consequence, alternative therapies based on the use of natural products, such as isoflavones, are in an experimental phase, but the data suggest that they could be used in the future as alternative therapies to ameliorate symptoms of natural and surgical menopause.

### **Acknowledgements**

The present chapter was realized with partial sources coming from Programa de Fortaleci‐ miento Académico del Posgrado de Alta Calidad, number: I010/458/2013, C-703/2013, and I010/152/2014, C-133/2014. The second and third authors received fellowships from the Consejo Nacional de Ciencia and Tecnología (CONACyT) for postgraduate studies in neuroethology (numbers 297410 and 297560, Respectively). The fourth author received financial support from CONACyT for Posdoctoral position at Universitary Center of Los Lagos, Universidad de Guadalajara.

### **Author details**

Juan Francisco Rodríguez-Landa1\*, Abraham Puga-Olguín2 , León Jesús Germán-Ponciano2 , Rosa-Isela García-Ríos2 and Cesar Soria-Fregozo3

\*Address all correspondence to: juarodriguez@uv.mx

1 Neuroethology Institute, Universidad Veracruzana. Xalapa, Veracruz, México.

2 Postgraduate Studies in Neuroethology, Institute of Neuroethology, Universidad Veracruzana. Xalapa, Veracruz, México

3 Laboratory of Psychobiology, University Center of Los Lagos, Universidad de Guadalajara. Lagos de Moreno, Jalisco, México

### **References**


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effects that limit their use in sensitive women. In consequence, alternative therapies based on the use of natural products, such as isoflavones, are in an experimental phase, but the data suggest that they could be used in the future as alternative therapies to ameliorate symptoms

The present chapter was realized with partial sources coming from Programa de Fortaleci‐ miento Académico del Posgrado de Alta Calidad, number: I010/458/2013, C-703/2013, and I010/152/2014, C-133/2014. The second and third authors received fellowships from the Consejo Nacional de Ciencia and Tecnología (CONACyT) for postgraduate studies in neuroethology (numbers 297410 and 297560, Respectively). The fourth author received financial support from CONACyT for Posdoctoral position at Universitary Center of Los Lagos, Universidad de

, León Jesús Germán-Ponciano2

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**Acknowledgements**

190 A Fresh Look at Anxiety Disorders

Guadalajara.

**Author details**

Rosa-Isela García-Ríos2

Juan Francisco Rodríguez-Landa1\*, Abraham Puga-Olguín2

\*Address all correspondence to: juarodriguez@uv.mx

Veracruzana. Xalapa, Veracruz, México

Lagos de Moreno, Jalisco, México

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### **Chapter 10**

**A Systematic Review of Anxiety Disorders following Mild, Moderate and Severe TBI in Children and Adolescents**

Michelle Albicini and Audrey McKinlay

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60426

#### **Abstract**

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198 A Fresh Look at Anxiety Disorders

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diol treatment. Brain Research, 2012; 1470:1–10.

The aim of this chapter is to systematically review the research exploring the relationship between TBI and anxiety disorders in children and adolescents. A literature search was conducted using Google Scholar, Ovid Medline (1946 - Dec 2013), PsycINFO (1806 - Dec 2013), CINAHL plus (1937 - Dec 2013), Cochrane database (2005 – Dec 2013) and Embase (1946 – Dec 2013). The search returned 346 articles, and 11 of these met the inclusion criteria. Anxiety disorders were often found to be a negative outcome following childhood TBI, with a higher incidence of disorders including GAD, ASD, PTSD, PD, OCD, simple/specific phobia, social phobia and SAD found in children following their injury. In most cases, this relationship was strongest for children with severe TBI who sustained their injury at a younger age. Psychosocial adversity was found to be a consistently significant predictor for the likelihood of children developing anxiety following TBI. It is concluded that children who have suffered from a TBI (mild, moderate or severe), are at a higher risk of developing subsequent anxiety disorders, even 1 year following the injury event, and children with more severe injuries, greater psychosocial adversity, and younger age at injury are considered to be the most vulnerable.

**Keywords:** traumatic brain injury, children, adolescents, anxiety disorders, risk 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.

### **1. Introduction**

Traumatic brain injury (TBI) is a common cause of morbidity and mortality worldwide, with prevalence estimates of 235 per 100,000 individuals in European countries having some form of TBI [1] and for children in particular, rates vary between 280-1373 per 100,000 across the world [2]. Considering the high rates of injury in children and young people, any accompa‐ nying long-term negative effects associated with such an injury are likely to represent a significant health concern and burden. Indeed, it is now well-documented that children with TBI may be at an increased risk of long-term, self-reported externalising behavioural problems including increased hyperactivity, aggression and conduct problems [3-8]. In addition to externalising behaviours, a higher incidence of diagnosed psychiatric disorders in children and adolescents following a TBI event has also been established, including Attention Deficit/ Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), Conduct Disorder (CD), drug abuse, and personality change disorders [9-10], compared to healthy controls and children with orthopedic injury (OI; an injury, such as fracture or break, to the bones excluding the head, neck or spinal cord [11]). In light of these ongoing problems children and young people may face following their TBI, a review and investigation is required to better under‐ stand the need for rehabilitation and recovery, and to understand the children at risk of these long-term effects.

### **2. Defining traumatic brain injury**

Traumatic brain injury (TBI) is defined as an injury to the head as a result of a blow or movement to the head and/or neck, following acceleration/deceleration impact, which causes neurological changes that affect normal brain functioning [12]. Severity of TBI therefore refers to the extent of neurological disruption that has occurred, and is classified as mild, moderate and severe [13]. The assessment of TBI severity is measured by the Glasgow Coma Scale (GCS), length of post-traumatic amnesia (PTA) and duration of loss of consciousness (LOC) [14-16]. The GCS is considered the best indicator of TBI severity, and evaluates three areas, including best motor and verbal responses, and eye opening [17]. Table 1 outlines the levels of severity for TBI and the respective definitions.


Note: Information in [13-14, 18]; GCS = Glasgow Coma Scale, LOC = loss of consciousness, PTA = post-traumatic amnesia.

**Table 1.** Defining severity levels of TBI

#### **2.1. Research findings**

**1. Introduction**

200 A Fresh Look at Anxiety Disorders

long-term effects.

**2. Defining traumatic brain injury**

for TBI and the respective definitions.

GCS = > 13 after 30 minutes LOC = < 30 minutes PTA = < 1 day

**Table 1.** Defining severity levels of TBI

Traumatic brain injury (TBI) is a common cause of morbidity and mortality worldwide, with prevalence estimates of 235 per 100,000 individuals in European countries having some form of TBI [1] and for children in particular, rates vary between 280-1373 per 100,000 across the world [2]. Considering the high rates of injury in children and young people, any accompa‐ nying long-term negative effects associated with such an injury are likely to represent a significant health concern and burden. Indeed, it is now well-documented that children with TBI may be at an increased risk of long-term, self-reported externalising behavioural problems including increased hyperactivity, aggression and conduct problems [3-8]. In addition to externalising behaviours, a higher incidence of diagnosed psychiatric disorders in children and adolescents following a TBI event has also been established, including Attention Deficit/ Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), Conduct Disorder (CD), drug abuse, and personality change disorders [9-10], compared to healthy controls and children with orthopedic injury (OI; an injury, such as fracture or break, to the bones excluding the head, neck or spinal cord [11]). In light of these ongoing problems children and young people may face following their TBI, a review and investigation is required to better under‐ stand the need for rehabilitation and recovery, and to understand the children at risk of these

Traumatic brain injury (TBI) is defined as an injury to the head as a result of a blow or movement to the head and/or neck, following acceleration/deceleration impact, which causes neurological changes that affect normal brain functioning [12]. Severity of TBI therefore refers to the extent of neurological disruption that has occurred, and is classified as mild, moderate and severe [13]. The assessment of TBI severity is measured by the Glasgow Coma Scale (GCS), length of post-traumatic amnesia (PTA) and duration of loss of consciousness (LOC) [14-16]. The GCS is considered the best indicator of TBI severity, and evaluates three areas, including best motor and verbal responses, and eye opening [17]. Table 1 outlines the levels of severity

**Mild TBI Moderate TBI Severe TBI**

GCS = 9-13 LOC = 30 minutes to 24 hours PTA = between 1 and 7 days

Note: Information in [13-14, 18]; GCS = Glasgow Coma Scale, LOC = loss of consciousness, PTA = post-traumatic amnesia.

GCS = ≤8 LOC = > 24 hours PTA = > 7 days

While it has been established that TBI is associated with an increased rate of externalising behavioural problems, there is a lack in the research exploring the incidence of internalising disorders, and in particular anxiety, following TBI in children. A couple of case studies report on individuals who developed new-onset anxiety symptomatology following TBI, which highlight the need for research in the area. For instance, an 11 year-old girl sustained a severe TBI following a fall from her bicycle, resulting in a coma for 16 days, and following resolution of PTA symptoms, the patient had developed new-onset compulsive behaviours including hand-washing, ordering, arranging and counting rituals [19]. Moreover, the symptoms appeared to worsen at a 6 month follow-up, which was subsequently treated with antidepres‐ sant medication [19]. Similarly, another case study reports on a patient who suffered from TBI requiring surgery at the age of 17 years, who reported the onset of social anxiety disorder (SAD) following their injury [20]. The male was previously characterised as extroverted and displayed no evidence of social anxiety. However, following the injury he became socially anxious which worsened until he sought treatment at 21 years, reporting difficulties with authority figures, unknown persons and people of the opposite sex [20]. Both of these afore‐ mentioned studies above highlight the important role of the frontal regions of the brain in that their damage following injury may precipitate anxiety symptomatology that is ongoing and requiring treatment or intervention [19-20].

Research exploring the incidence of novel post-injury psychiatric disorders and behavioural problems following TBI in children suggests a greater need for information about the onset of anxiety disorders in the TBI population. There have been reports of rates of novel anxiety disorders in 15% of children with TBI compared to 7.5% of an OI control group [10]. Further, anxiety has been found to occur in higher rates than ADHD and ODD [10]. In children with mild TBI, up to 36% of individuals have been found to exhibit specific anxiety disorders 6 months post-injury [9]. This finding is also evident in other samples for children with mild-TBI, with increased rates on anxious/depressed self-report items on a behavioural rating scale as compared to children with no injury [4]. Others however have reported on different findings. For instance, in an assessment of long-term psychiatric outcomes following preschool mild TBI, no significant difference in the incidence of anxiety disorders were found between individuals with and without TBI when they reached adolescence [7]. Further, while parent reports of behaviour following severe TBI in children has indicated elevated rates of anxiety, the relationship was weak compared to that of ADHD and other externalising problems [21]. Differences in reported outcomes may be due to the length of time that assessments took place post-injury, or in differences in the tools used to evaluate problems. Despite the mixed results, there have been reports of heightened anxiety symptoms following TBI in children and adolescent samples [9-10, 21].

Brain imaging studies further support the potential relationship between an increased incidence of anxiety disorders following TBI in children and adolescents, however again the literature is sparse. While it has been stated that frontal and temporal regions are the most susceptible to impact during a TBI [22], it has been found that deep-brain structures such as the amygdala and hippocampus are also highly vulnerable to such an injury [22]. Indeed, the amygdala has been targeted as an important region in children for processing fearful facial expressions and producing rapid protective responses [23]. Further, right and left amygdala volumes have been found to be significantly larger in children with anxiety [24]. These findings have potential implications for literature involving anxiety and TBI in children and adoles‐ cents. Considering the discrepancies in the research mentioned above, and the fact that specific anxiety disorders are rarely the focus of interest in studies exploring the long-term and acute effects of TBI, it is important to review the literature and examine avenues for future research.

#### **2.2. Rationale and aims**

It is clear that anxiety negatively affects all areas of function, which is particularly important in the case of children, who are in a rapid state of developmental change. As outlined above, a TBI event can disrupt the developing systems in the brain. Further, research has shown that exposure to events that produce chronic anxiety can have long-term consequences by disrupt‐ ing the developing architecture of the brain [25-26]. It is therefore important that we under‐ stand the impact of anxiety on outcomes following TBI in childhood as this will provide a platform for appropriate intervention to promote a more positive result.

As stated above, the incidence, rate and profile of internalising disorders following TBI in children has been relatively overlooked in the literature when compared to that of externalising disorders. Internalising behaviours represent internal states of distress, whereas externalising behaviours are directed outwardly and therefore tend to be more visibly distressing [27]. This difference in presentation of difficulties may contribute to the lack of research in internalising disorders, given that externalising problems experienced by children following TBI may be more readily reported by parents. The fact that males present with higher rates of TBI than females [28-29] may contribute to this difference, considering that externalising disorders tend to be more common in males than females [27, 30], while females are more likely to report internalising problems [30]. It is evident therefore that there may be a bias in the literature with regards to female oriented behavioural outcomes following TBI, with internalising problems (particularly anxiety) being significantly overlooked.

Based on the literature, this chapter will systematically review original research studies up until 2013 that have explored the relationship between TBI and anxiety disorders in children and adolescents. A comprehensive review investigated the cognitive, behavioural and academic outcomes of mild TBI in children and adolescents, and the merit of each study was strategically analysed according to specified criteria [31]. The rationale behind this procedure was due to the wide variability in methodology for past studies involving mild TBI.

The key criteria set out as essential for studies in this area were as follows:


A study was concluded to have methodological merit if it met at least four of the previously listed criteria [31]. For this review, the methodology of the selected papers was examined according to these criteria, with the inclusion of moderate and severe injuries. When consid‐ ering anxiety disorders, this refers to disorders including Generalised Anxiety Disorder (GAD), Post-Traumatic Stress Disorder (PTSD), Social Anxiety Disorder (SAD), Obsessive-Compulsive Disorder (OCD), Acute Stress Disorder (ASD), simple/specific phobia, social phobia and Panic Disorder (PD). Search methods and results will be outlined, and methodo‐ logical considerations and future directions will be discussed and explored.

#### **2.3. Comparison of merit of studies with criteria from Satz (2001)**

expressions and producing rapid protective responses [23]. Further, right and left amygdala volumes have been found to be significantly larger in children with anxiety [24]. These findings have potential implications for literature involving anxiety and TBI in children and adoles‐ cents. Considering the discrepancies in the research mentioned above, and the fact that specific anxiety disorders are rarely the focus of interest in studies exploring the long-term and acute effects of TBI, it is important to review the literature and examine avenues for future research.

It is clear that anxiety negatively affects all areas of function, which is particularly important in the case of children, who are in a rapid state of developmental change. As outlined above, a TBI event can disrupt the developing systems in the brain. Further, research has shown that exposure to events that produce chronic anxiety can have long-term consequences by disrupt‐ ing the developing architecture of the brain [25-26]. It is therefore important that we under‐ stand the impact of anxiety on outcomes following TBI in childhood as this will provide a

As stated above, the incidence, rate and profile of internalising disorders following TBI in children has been relatively overlooked in the literature when compared to that of externalising disorders. Internalising behaviours represent internal states of distress, whereas externalising behaviours are directed outwardly and therefore tend to be more visibly distressing [27]. This difference in presentation of difficulties may contribute to the lack of research in internalising disorders, given that externalising problems experienced by children following TBI may be more readily reported by parents. The fact that males present with higher rates of TBI than females [28-29] may contribute to this difference, considering that externalising disorders tend to be more common in males than females [27, 30], while females are more likely to report internalising problems [30]. It is evident therefore that there may be a bias in the literature with regards to female oriented behavioural outcomes following TBI, with internalising problems

Based on the literature, this chapter will systematically review original research studies up until 2013 that have explored the relationship between TBI and anxiety disorders in children and adolescents. A comprehensive review investigated the cognitive, behavioural and academic outcomes of mild TBI in children and adolescents, and the merit of each study was strategically analysed according to specified criteria [31]. The rationale behind this procedure

was due to the wide variability in methodology for past studies involving mild TBI.

The key criteria set out as essential for studies in this area were as follows:

platform for appropriate intervention to promote a more positive result.

(particularly anxiety) being significantly overlooked.

**b.** longitudinal design with follow-up assessments,

**e.** outcome measures involved standardised tests, and

**d.** inclusion of at least 20 participants with TBI,

**2.2. Rationale and aims**

202 A Fresh Look at Anxiety Disorders

**a.** Use of control group,

**c.** clear definition of mild TBI,

**f.** control for pre-injury factors [31].

As mentioned above, a prior literature review examined research studies investigating behavioural problems following mild TBI, and set out criteria regarding what constitutes as a study that has 'methdological merit' [31]. This method was utilised here, and each paper generated from the literature search was analysed according to the review's criteria. The results of the analysis can be found in Table 2 below.



**Table 2.** Literature search results based on research methodology criteria

As is evident in Table 2, in accordance to the criteria set out by the review [31], all of the studies involving anxiety disorders following TBI in children and adolescents had methodological merit, possessing at least four of the essential criteria. A discussion of this analysis will be provided later in the chapter.

### **3. Method**

A systematised literature search was conducted using the following search engines: Google Scholar, Ovid Medline (1946 - Dec 2013), PsycINFO (1806 - Dec 2013), Comprehensive Journal Index and Additional Resources for Nursing and Allied Health Professionals (CINAHL) plus (1937 - Dec 2013), Cochrane database (2005 – Dec 2013) and Embase (1946 – Dec 2013). A search was conducted in each database using the terms "traumatic brain injury" or "brain injury" or "head injury" and "anxiety disorders" or "anxiety" and "pediatric" or "paediatric" or "children" or "child". Returned articles were screened by title, abstract or full-text accordingly. Manual searching of articles based on the reference lists of relevant manuscripts was also conducted.

Inclusion criteria for studies were as follows:


Exclusion criteria involved:


### **4. Results**

The search returned a total of 346 articles. Of these, 221 were screened by title, and 82 were screened based on abstract. The full text was examined for 43 of the articles. Of the articles examined by full text, 32 of these were excluded for the following reasons: not an original research paper (n=6), case study (n=1), not specifically assessing anxiety as an outcome measure (n=21), not assessing TBI participants (n=3), or couldn't access the article (n=1). Manual searching of additional studies using the reference lists of relevant articles was conducted, however no further studies were found. The final result included 11 research studies fitting the above criteria, for which study characteristics and findings are outlined in Table 3.

#### **4.1. Anxiety disorders following TBI in children and adolescents**

**a) Use of control group**

**[40] Vasa et al. (2002)**

204 A Fresh Look at Anxiety Disorders

**[41] Vasa et al. (2004)**

**3. Method**

conducted.

**4. Results**

provided later in the chapter.

Inclusion criteria for studies were as follows:

**b.** the study included a TBI group, and

Exclusion criteria involved:

**a.** Participants were children aged 0-18 years,

**b.** participants with acquired brain injury (ABI).

**a.** Adult participants or a mixture of children and adults, and

**b) Longitudinal design with follow-up**

**Table 2.** Literature search results based on research methodology criteria

**c) Clear definition of TBI**

As is evident in Table 2, in accordance to the criteria set out by the review [31], all of the studies involving anxiety disorders following TBI in children and adolescents had methodological merit, possessing at least four of the essential criteria. A discussion of this analysis will be

A systematised literature search was conducted using the following search engines: Google Scholar, Ovid Medline (1946 - Dec 2013), PsycINFO (1806 - Dec 2013), Comprehensive Journal Index and Additional Resources for Nursing and Allied Health Professionals (CINAHL) plus (1937 - Dec 2013), Cochrane database (2005 – Dec 2013) and Embase (1946 – Dec 2013). A search was conducted in each database using the terms "traumatic brain injury" or "brain injury" or "head injury" and "anxiety disorders" or "anxiety" and "pediatric" or "paediatric" or "children" or "child". Returned articles were screened by title, abstract or full-text accordingly. Manual searching of articles based on the reference lists of relevant manuscripts was also

**c.** anxiety symptoms or anxiety disorder diagnosis was included as an outcome measure.

The search returned a total of 346 articles. Of these, 221 were screened by title, and 82 were screened based on abstract. The full text was examined for 43 of the articles. Of the articles

**d) At least 20 TBI participants**

√ √ √ √ √

√ √ √ √ √

**e) Standardised tests used**

**f) Controlled for pre-injury factors**

> As is evident in Table 3, results from the studies generally reveal some relationship between the presence of anxiety disorders following TBI in children and adolescents. The majority of studies focused on correlates of PTSD following childhood TBI [11, 32-36], with generally mixed but similar findings. The focus on PTSD in such a sample is unsurprising given the close link between such an injury and trauma. Main findings indicate that PTSD within 1 year following TBI can occur despite experiencing post-traumatic amnesia (PTA) [32-33], and that PTSD symptomatology is more prominent in children with severe TBI than those with moderate TBI or OI [33]. Analysis of factors that can predict the development of PTSD in children following TBI reveal that levels of PTSD symptoms are related to social disadvantage/ family social status [33-34], anxiety diagnoses and aggregate anxiety scores [34], other psychiatric diagnoses and symptoms [34] and the presence of internalising disorders at time of injury [32]. Furthermore, predicting the diagnosis of PTSD following TBI was significantly related to anxiety diagnoses and scores, depression symptoms and non-anxiety psychiatric diagnoses [34]. When examining gender differences, female gender was a significant predictor of PTSD in one study [34], however was not the case for other investigators [32]. It is interesting to note that gender was unexamined in one study [33] considering anxiety disorders are seen in higher rates in a female population, it would be beneficial to the literature to compare anxiety symptomatology among groups.

> Conversely, two studies exploring the relationship between PTSD and TBI report on different findings. One study explored PTSD following road traffic accidents in children with OI and mild TBI [36], and the other assessed the relationship between post-concussion symptoms (PCS) and PTSD in children with mild TBI and OI [11], with both papers reporting no signif‐ icant difference among the sample groups on levels of PTSD symptomatology. This result may suggest that those with milder TBI are no more likely to develop PTSD following their injury than children who have sustained an OI. However, differences in the presentation of PTSD symptomatology following injury were found among the two papers. In [11], children with mild TBI tended to report a more frequent occurrence of mild PTSD symptoms, whereas severe PTSD occurred at a higher rate in the OI group. Moreover, another found that those in the mild TBI group reported higher levels of hyperarousal at 3 and 12 months, but not when controlling for PCS, whereas OI participants had higher levels of PTSD when controlling for baseline PCS and were more likely to meet PTSD criteria [26]. Therefore, these findings indicate that while there were no differences in the rate of PTSD symptomatology and diagnoses between mild TBI and OI children, the clinical manifestations of such symptomatology may be quite different across groups. Again, neither study examined any influence of gender on the likelihood of developing PTSD following TBI.



**Authors**

**[32] Max et al.**

Identify PTSD and PTSD

50 consecutively

Severe injury = Glasgow

Coma Scale (GCS) score ≤

admitted TBI patients

aged 6-14 years at TOI

8


Moderate injury = GCS

score 9-12 or 3-15 with

positive CT scan

Mild injury = GCS score

13-15

TBI, 15 severe TBI


symptomatology

following TBI

Determine predictors of

PTSD following TBI

**(1998)**

 **Aims**

**Participants**

**Classifying TBI Severity**

 **Inclusion/**

**Anxiety Measures**

**General Results**

**Exclusion Criteria**

Inclusion: admitted to

Neuropsychiatry Rating

2/50 with PTSD (resolved by 3

tertiary care centre and 3

Scale (NRS)

months)

Increase in PTSD symptoms in first

206 A Fresh Look at Anxiety Disorders

3 months, then gradual decline

68% experienced ≥ 1 PTSD symptom

at any point in first 3 months; 45%,

33%, 16% and 12% at 3, 6, 12 and 24

Baseline:


Disorders and

Schizophrenia for

School-Age Children –

Epidemiologic version

months

Presence of internalising disorders,

and severity of injury were main

predictors of PTSD

(K-SADS-E) plus PTSD

module

Follow-ups:


on ADHD, ODD, CD,

alcohol and substance

abuse and PTSD module

Child PTSD Index

Parent reports for moderate TBI and

OI in doubtful range for PTSD; mild

levels PTSD reported for severe TBI

at 6- and 12-months

PTSD symptoms reported as higher

for severe TBI group

Younger age and higher social

disadvantage associated with more

PTSD symptoms

Children displayed PTSD

symptoms for >1 year post-TBI

13% sample developed PTSD within

(CPTSDRI) (child report)

Post Traumatic Stress

Scale (PTSS) (parent

**[33] Levi &**

Explore PTSD symptoms

Children 6-12 years at

Severe TBI = GCS score ≤

Inclusion: hospitalised ≥1

night, participants from a

prospective study on

impact of TBI, English as

primary language

report)

Exclusion: history of

child abuse, TBI or brain

disease, children with

brain injuries other than

closed head injury (e.g.

anoxic injuries)

Inclusion: children

Baseline:


1 year of TBI


child reports and 2 to both

Premorbid anxiety symptoms

predisposed participants to PTSD

symptoms 1 year post TBI

Risk factors for PTSD and PTSD

symptoms: female gender, high

psychosocial adversity, greater

for Children and

Adolescents parent form

(DICA-p)


Checklist (CBCL)


retrospectively of

premorbid behavior

admitted to

neurorehabilitation unit

of university-affiliated

center

Exclusion: previous

hospitalisations for TBI,

premorbid PTSD,

premorbid mental

retardation or CNS

in children who have

TOI

8

Moderate TBI = GCS

score 9-12, or >12 plus

positive CT scans or LOC

> 15mins

81 TBI children



59 OI children


experienced traumatic

injuries

Compare PTSD

symptoms of children

with TBI and OI

**[34] Gerring**

Examine the presence

95 children aged 4-19

GCS score of 3-8

indicated severe TBI

classification

years with severe TBI

and PTA


and rate of PTSD

diagnosis and PTSD

symptomatology

following TBI

years



outpatient

**et al. (2002)**

**Drotar (1999)**

regional hospitals, CT

scan on admission,

English spoken language

Exclusion: PTA > 3

months, penetrating TBI,

documented history of

child abuse and/or TBI

involving hospital

admission, history of

CNS disorders, preexisting serious illness



**Authors**

**[40] Vasa et**

Compare rate of pre- and

97 children aged 4-19

GCS score of ≤8 taken at

Inclusion: referred from

DICA-p assessed anxiety

disorders at baseline and

1-year follow-up


each anxiety disorder in

reported ≥10


reported 4-9 and 12% reported ≥10


that had 4-9 and more than 10

symptoms

Pre-injury anxiety and younger age

at injury risk factors for post-injury

anxiety

tertiary trauma centres

and recruited from

consecutive admissions

from 1992-1996 to

neurorehabilitation unit

addition

of university-affiliated

center

Exclusion: previous

hospitalisations or

emergency room visits

for TBI, history of child

abuse, premorbid mental

retardation or CNS

pathology

Inclusion: enrolled in

CPTSDRI – children

No significant differences between

groups for PTSD symptomatology

69% no-TBI and 85.7% TBI group

suffered from PTSD

Mean scores indicated

improvements in PTSD symptoms

Presence of PTSD strongly

associated with anxiety

Child and parent report of PTSD not

significantly correlated

report of PTSD

Revised Children's

Manifest Anxiety Scale

(RCMAS) – child report

of anxiety

PTSD module of Anxiety

Disorders Interview

Schedule-child version

(ADIS-c) – parent report

normal stream school,

involved in recent traffic

accident, sustained an

injury other than TBI or a

**[36] Mather et**

Compare the presence of

43 children from

Mild TBI defined by:



medical file


after 24 hours

TBI

Exclusion: prior TBI

history, current TBI of

moderate or severe

classification, limited

English comprehension

or PTSD

CBCL

of families

Inclusion: referred from

MR Imaging conducted 3

12 subjects had 1 post-injury

disorder, 1 had 2 disorders: 6 simple

months post-TBI

tertiary trauma centres

and recruited from

Casualty section of

Sydney hospital aged

6-16 years



PTSD in children who

have been in a traffic

accident with and

without mild TBI

Compare child and

parent reports of PTSD

following the accident

**[41] Vasa et**

Examine whether

97 children aged 4-19

Initial GCS score on

admission of ≤ 8

years with severe TBI


damage to specific brain

regions are associated

**al. (2004)**

**al. (2003)**

admission indicated

severe TBI

years with severe TBI



**al. (2002)**

post-TBI anxiety

disorders and symptoms

Examine relationship

between risk factors and

years

anxiety outcomes

following TBI

 **Aims**

**Participants**

**Classifying TBI Severity**

 **Inclusion/**

**Anxiety Measures**

**General Results**


severe


208 A Fresh Look at Anxiety Disorders

OI, 35.7% mild, 63.2%

moderate/severe

Mean aggregate Anxiety score of

1.86 pre-injury and 3.73 post-injury


symptoms, 13% reported 4-9, and 3

**Exclusion Criteria**


**Table 3.** Characteristics of studies from literature search presented in order of study recency

Compulsive Disorder; ASD = Acute Stress Disorder; OFC = Orbitofrontal Cortex; PCS = post-concussion symptoms

When focusing on the incidence and presentation of anxiety disorders in general, only four studies were found relevant. One study focused on the incidence of OCD and presence of OCD symptomatology following severe TBI in children and adolescents [37], while the remaining studies explored the relationship between TBI and the incidence of disorders including GAD, ASD, PTSD, PD, OCD, simple/specific phobia, social phobia and SAD [38-40]. Only two studies included participants with mild, moderate and severe TBI [38-39], while the rest focused on severe TBI [37, 40]. Generally, the results demonstrate that in children and adolescents who have sustained aTBI of any severity, there is a statistically significant higher risk of developing subsequent anxiety disorders [37-40].

Overanxious (heightened anxiety which is generalised and non-specific) was a commonly reported disorder in children with severe TBI [40], and the presence of OCD symptomatology following severe TBI was significantly more common in females. When comparing children with mild TBI, moderate/severe TBI and OI, results suggest a potential relationship between degree of neurological insult and risk of developing subsequent anxiety disorders [38], in that overall anxiety disorders were most common in children with moderate/severe TBI, followed by mild TBI and OI. However, similarly to research on PTSD after TBI, the pattern of results is often quite different among the sample groups, including differing age ranges, varying use of control groups, and severity of TBI. For instance, a few of the studies [37, 39-40] didn't use any comparison group when examining rates of anxiety symptomatology and diagnoses, and as such the conclusion that such diagnoses are heightened in a TBI sample is relatively weak, as compared to another study [38] which compared incidence of anxiety diagnoses to an OI comparison group. In terms of gender differences, among two of the studies, gender as a predictor was either not considered [38] or not discussed in any detail [39-40]. Only one study found that being female was associated with a higher number of obsessive compulsive symptoms, with a greater number of females reporting obsessive compulsive symptoms following TBI [37].


<sup>⋅</sup> Internalising disorders [32, 34, 37]


**Authors**

 **Aims**

**Participants**

**Classifying TBI Severity**

 **Inclusion/**

**Anxiety Measures**

**General Results**

After controlling for PCS, OI group

reported higher scores on PCL-C/PR

than mild TBI group at baseline

210 A Fresh Look at Anxiety Disorders

Symptoms of PTSD and PCS

correlated more highly for OI group

than mild TBI

**Exclusion Criteria**

previous TBI needing

hospitalisation,

premorbid neurological

disorders, severe

psychiatric disorder

needing hospitalisation,

AIS of greater than 3,

injuries that would

hinder assessment, child

abuse/neglect

Inclusion: Consecutive

DSM-IV diagnoses

8.5% developed novel clinical

anxiety disorder and 17%

developed novel subclinical anxiety

disorder post-TBI


subclinical anxiety


subclinical anxiety


subclinical anxiety

9 PTSD, 6 SAD, 4 simple phobia, 3

GAD, 3 adjustment disorder with

anxious mood, 3 social phobia, 1

panic disorder

Younger age at injury associated

with novel anxiety disorder

Note. PTSD = Post-Traumatic Stress Disorder; TBI = traumatic brain injury; TOI = time of injury; CT = computed tomography; PTA = post-traumatic amnesia; CNS = central nervous system;

ADHD = Attention-Deficit/Hyperactivity Disorder; ODD = Oppositional Defiant Disorder; CD = Conduct Disorder; OI = orthopaedic injury; LOC = loss of consciousness; MR = magnetic

resonance; DSM-IV = Diagnostic and Statistical Manual for Mental Disorders fourth edition; SAD = separation anxiety disorder, GAD = Generalised Anxiety Disorder; OCD = Obsessive-

Compulsive Disorder; ASD = Acute Stress Disorder; OFC = Orbitofrontal Cortex; PCS = post-concussion symptoms

**Table 3.** Characteristics of studies from literature search presented in order of study recency

derived from KSADS

present and lifetime

version, and NRS

MR Imaging scans at 3

admissions to 3 academic

medical centres for TBI

between 1998-2003

Exclusion: pre-existing

autism, ADHD or

months

schizophrenia, mental

deficiency, injury due to

child abuse or

penetrating injury

**[39] Max et al.**

Examine the rate and

177 children aged 5-14

GCS scores of 3-8 for

severe TBI, 9-12 for

moderate TBI and 13-15

for mild TBI


years with TBI


64 severe


nature of novel anxiety

disorders and novel

subclinical anxiety

disorders in children

following TBI

years


**(2011)**


**Table 4.** Predictors and risk factors for anxiety following TBI

<sup>⋅</sup> Severity of TBI [32, 34, 38]

<sup>⋅</sup> Younger age at injury [33, 39, 40]

Among the research, common themes exist in reference to the relationship between anxiety disorders and TBI in children and adolescents. A number of the studies presented here assessed for pre-morbid psychosocial adversity, with all studies reporting higher rates of anxiety and PTSD symptomatology and diagnoses in children from families with higher pre-morbid psychosocial adversity [34-35, 37, 40-41]. In addition, when the impact of age was assessed within the methodology, it was found that younger age at injury tended to be associated with a higher number of anxiety symptoms [33, 39-40] in such children. Alternatively however, there have been conflicting results, in that one found no support for age as a significant predictor of PTSD in their sample of children with severe TBI [34]. This is comparative to results found in a sample of children with mild, moderate and severe TBI, whereby younger age was associated with a higher number of PTSD symptoms [33]. This may be accounted for by the fact that in [34], the researchers utilised a large age range of participants (4-19 years), versus the other study which restricted their sample to children aged 6-12 years [33]. The implications of age ranges utilised in the study samples is discussed further below. See Table 4 for the predictors and risk factors for children and adolescents to develop anxiety disorders and symptomology following TBI.

#### **4.2. Neural substrates and brain regions associated with anxiety following TBI**

In examining the brain regions associated with a higher risk of anxiety following child‐ hood TBI, it is important to first review the areas of the brain that are commonly injured and implicated in TBI. Damage as a result of TBI can be either focal, whereby forces have caused localised damage, or diffuse, whereby damage has occurred to axonal properties across the brain [42-43]. Due to the fact that TBI can occur under many different, individu‐ alised circumstances, damage to the brain is heterogeneous [44]. However, it has been noted that the frontal and temporal regions are highly vulnerable to injury, due to the shape of the skull and the way the head is held [22, 44-46]. The frontotemporal susceptibility to damage from TBI has been noted as the major cause of the cognitive and neurobehavio‐ ral consequences of TBI that some go on to experience, including emotional regulation [45]. Further, white matter tracts have been demonstrated to be more susceptible to damage due to the acceleration-deceleration forces and their direct exposure to shear and strain forces [43-44, 47], and this white matter tract damage tends to occur more frequently again within the frontotemporal areas of the brain [44].

Due to the diffuse damage likely to occur following TBI, and the heterogeneity that occurs across individuals, research has sought to explore and highlight the most commonly affected regions within the brain that may be associated with long-term behavioural and emotional problems. Reports from a multicentre study of children with TBI have noted white matter hypersensitivities and focal atrophy distributed across frontotemporal areas of the brain [44]. More specifically, Magnetic Resonance Imaging (MRI) scans highlighted that among children with mild, moderate and severe TBI, there were lesions evident in frontal regions, temporal poles, and right medial temporal lobe, and damage was also evident to the amygdala, hippocampus, thalamus and basal ganglia [44]. MRI procedures were also used in another sample of children with moderate and severe TBI, to evaluate brain volume differences in the whole brain and also prefrontal, temporal and posterior regions [22]. Imaging results indicated that children with TBI had significantly reduced whole brain, prefrontal and temporal regional tissue volumes compared to that of uninjured children. Further, there were also group differences on white matter and grey matter in superior medial and ventromedial prefrontal regions [22]. Additional research has also utilised MRI procedures to locate brain regions more commonly affected following TBI, with one study including individuals with mild to moderate TBI [46]. In terms of number of lesions, results showed that the frontal and temporal areas had significantly more lesions than parietal and occipital areas of the brain. Again, this is supported by the Toronto TBI study, which recruited individuals with chronic TBI across all levels of severity to undergo MRI 1 year following injury [42]. The most reliable effects noted in the results were brain volume changes within the frontal, temporal and cingulate regions, with focal lesions associated with greater volume loss in frontal and temporal regions [42]. Finally, MRI has been used to examine reductions in fractional anisotropy (reflects fibre density, axonal diameter and myelination in white matter) in adults with mild TBI [47]. Results again dem‐ onstrated more reductions in frontal and temporal regions, and also parietal regions, and among association bundles, fronto-temporal-occipital fibre bundles were most often involved [48]. Table 5 provides a concise summary of the above findings within the literature.

Among the research, common themes exist in reference to the relationship between anxiety disorders and TBI in children and adolescents. A number of the studies presented here assessed for pre-morbid psychosocial adversity, with all studies reporting higher rates of anxiety and PTSD symptomatology and diagnoses in children from families with higher pre-morbid psychosocial adversity [34-35, 37, 40-41]. In addition, when the impact of age was assessed within the methodology, it was found that younger age at injury tended to be associated with a higher number of anxiety symptoms [33, 39-40] in such children. Alternatively however, there have been conflicting results, in that one found no support for age as a significant predictor of PTSD in their sample of children with severe TBI [34]. This is comparative to results found in a sample of children with mild, moderate and severe TBI, whereby younger age was associated with a higher number of PTSD symptoms [33]. This may be accounted for by the fact that in [34], the researchers utilised a large age range of participants (4-19 years), versus the other study which restricted their sample to children aged 6-12 years [33]. The implications of age ranges utilised in the study samples is discussed further below. See Table 4 for the predictors and risk factors for children and adolescents to develop anxiety disorders and

**4.2. Neural substrates and brain regions associated with anxiety following TBI**

In examining the brain regions associated with a higher risk of anxiety following child‐ hood TBI, it is important to first review the areas of the brain that are commonly injured and implicated in TBI. Damage as a result of TBI can be either focal, whereby forces have caused localised damage, or diffuse, whereby damage has occurred to axonal properties across the brain [42-43]. Due to the fact that TBI can occur under many different, individu‐ alised circumstances, damage to the brain is heterogeneous [44]. However, it has been noted that the frontal and temporal regions are highly vulnerable to injury, due to the shape of the skull and the way the head is held [22, 44-46]. The frontotemporal susceptibility to damage from TBI has been noted as the major cause of the cognitive and neurobehavio‐ ral consequences of TBI that some go on to experience, including emotional regulation [45]. Further, white matter tracts have been demonstrated to be more susceptible to damage due to the acceleration-deceleration forces and their direct exposure to shear and strain forces [43-44, 47], and this white matter tract damage tends to occur more frequently again within

Due to the diffuse damage likely to occur following TBI, and the heterogeneity that occurs across individuals, research has sought to explore and highlight the most commonly affected regions within the brain that may be associated with long-term behavioural and emotional problems. Reports from a multicentre study of children with TBI have noted white matter hypersensitivities and focal atrophy distributed across frontotemporal areas of the brain [44]. More specifically, Magnetic Resonance Imaging (MRI) scans highlighted that among children with mild, moderate and severe TBI, there were lesions evident in frontal regions, temporal poles, and right medial temporal lobe, and damage was also evident to the amygdala, hippocampus, thalamus and basal ganglia [44]. MRI procedures were also used in another sample of children with moderate and severe TBI, to evaluate brain volume differences in the

symptomology following TBI.

212 A Fresh Look at Anxiety Disorders

the frontotemporal areas of the brain [44].

As is evident, the frontal and temporal regions are highly implicated following TBI of all severities. In looking at the neural regions implicated in those with anxiety disorders following TBI, it may be possible to discover overlapping regions. However, only two studies have specifically attempted to delineate the neural correlates and brain regions involved in the development of anxiety disorders following TBI in children and adolescents [35, 40]. One of these studies focused on lesion burden in children with severe TBI and their relationship with PTSD symptomatology [35]. Data was obtained from a cohort from a pre-existing study [34], which utilised participants with only severe TBI, and did not include any comparison group. Magnetic Resonance Imaging (MRI) at 3 months following the TBI event revealed associations between lesion fractions in the right cingulum, right hippocampus, right medial frontal gyrus and left hippocampus at 3 months post-TBI, and the presence of PTSD re-experiencing symptoms at 1 year [35]. In addition, assignment to the PTSD versus no-PTSD diagnosis group was dependent on lesions in the right medial frontal and left middle temporal gryi [35]. Furthermore, a lower probability of suffering from PTSD hyperarousal correlated with higher lesion fraction in the left subcallosal gyrus, and avoidance symptoms were associated with lower lesion burden in the right medial frontal and left inferior temporal gyri and higher lesion burden in the left middle temporal gyrus [35]. Interestingly, the researchers found no associ‐ ation between the re-experiencing criterion of PTSD and lesions in the right amygdala, despite research which has suggested that the amygdala is an important structure in the processing of fear and emotional signals [23], and in anxiety symptoms [24].

Again utilising the same cohort of participants in [34], the incidence and presence of anxiety disorders in general and their neural correlates in patients with severe TBI was examined, using MRI procedures [41]. The study was unique in that it attempted to correlate specific brain lesions and their location, with different anxiety outcomes among children with severe TBI. In a 1-year prospective study, with a focus on the orbitofrontal cortex (OFC), imaging results


**Table 5.** Summary of commonly damaged brain regions following TBI

revealed that the presence of OFC lesions decreased the risk of anxiety disorders when control variables (demographics, psychosocial adversity, preinjury anxiety, injury severity, postinjury PTSD, whole brain volume) were included in the analyses [41]. Therefore, an inverse relationship exists in that children with more lesions to the OFC as a result of TBI are less likely to develop anxiety disorders than those with fewer lesions. This is said to be due to a disruption between the OFC and amygdala, which results in a disrupted ability to modify responses to cues based on processing the emotional valence of a stimulus [41].The OFC is purported to have important reciprocal connections with the amygdala [41], which again further supports the brain region studies which target the amygdala in having some role in anxiety disorders in children [23-24].

In addition, two other studies included MRI procedures in their methodology - however brain lesion analysis was not a major aim of their study [33, 37, 39]. In examining the nature of OCD symptomatology in children and adolescents with a history of severe TBI, some specific areas were located to potentially be associated with the onset of OCD symptomatology following TBI [37]. MRI scans revealed relationships between OCD symptoms and lesions in the OFC and temporal lobe regions, and also thalamic lesions for males [37]. Alternatively, in their study of anxiety disorders in children and adolescents following severe TBI [39], it was reported that a trend association exists between lesions to the superior frontal gyrus and the presence of novel anxiety disorders. Furthermore, a statistically significant association was found between lesions to the superior frontal gyrus and novel subclinical anxiety disorder [39]. However, no other statistically significant relationships between specific brain lesions and anxiety sympto‐ matology were found in the study.

The above studies implicate certain regions in relation to the elevated incidence of anxiety disorders following TBI in children and adolescents, with emphasis on structures such as the OFC, right medial frontal gyri and temporal gyri. Table 3 outlines the specific regions impli‐ cated in anxiety following TBI from the literature. Evidently, these findings highlight a link with commonly affected brain regions following TBI, where research has implicated areas associated with the frontal and temporal regions. While these studies provide some compelling initial evidence for the neurobiological basis of anxiety disorders following TBI, it is clear that the literature in this area is still very sparse and lacking.


**Table 6.** Brain regions associated with anxiety in children and adolescents with TBI

### **5. Discussion**

revealed that the presence of OFC lesions decreased the risk of anxiety disorders when control variables (demographics, psychosocial adversity, preinjury anxiety, injury severity, postinjury PTSD, whole brain volume) were included in the analyses [41]. Therefore, an inverse relationship exists in that children with more lesions to the OFC as a result of TBI are less likely to develop anxiety disorders than those with fewer lesions. This is said to be due to a disruption between the OFC and amygdala, which results in a disrupted ability to modify responses to cues based on processing the emotional valence of a stimulus [41].The OFC is purported to have important reciprocal connections with the amygdala [41], which again further supports the brain region studies which target the amygdala in having some role in anxiety disorders

In addition, two other studies included MRI procedures in their methodology - however brain lesion analysis was not a major aim of their study [33, 37, 39]. In examining the nature of OCD symptomatology in children and adolescents with a history of severe TBI, some specific areas were located to potentially be associated with the onset of OCD symptomatology following TBI [37]. MRI scans revealed relationships between OCD symptoms and lesions in the OFC

in children [23-24].

**Study Main results**

Number of lesions from MRI:

MRI volumetric findings:

grey matter smaller in TBI group ⋅ Lesion volumes from MRI:

⋅ Frontal lobe = 42 individuals (22%) ⋅ Parietal lobe = 31 individuals (16%) ⋅ Temporal lobe = 28 individuals (15%) ⋅ Occipital lobe = 4 individuals (2%)

thalamus, basal ganglia

**Table 5.** Summary of commonly damaged brain regions following TBI

frontal and temporal lobe regions

⋅ Prefrontal regions smaller in those with TBI

⋅ Majority lesions in frontal and temporal areas

⋅ Volume changes in ventral frontal and temporal regions

Brain regions with reduced fractional anisotropy from MRI:

⋅ Superior medial grey and white matter, lateral frontal white matter, and ventromedial

⋅ Cerebrospinal fluid increases in left medial frontal and posterior temporal regions ⋅ Grey matter volume changes in ventral frontal, middle frontal, superior frontal, bilateral posterior temporal, left medial temporal, left occipital and basal ganglia/thalamic regions

⋅ Distribution of lesions was more frequent in frontal and temporal regions

⋅ Mean group volume differences for white matter, grey matter, hippocampus, amygdala,

⋅ Focal signal abnormalities and white matter hypersensitivities located predominantly in

⋅ Total = 145 ⋅ Frontal = 60 ⋅ Temporal = 55 ⋅ Parietal = 15 ⋅ Occipital = 10

**[46] Levin et al. (1992)**

214 A Fresh Look at Anxiety Disorders

**[22] Wilde et al. (2005)**

**[42] Levine et al. (2008)**

**[47] Rutgers et al. (2008)**

**[44] Bigler et al. (2013)**

The above literature demonstrates that the presence of mild, moderate and severe TBI in children and adolescents significantly increases the risk of developing subsequent anxiety disorders [37-40], with feeling overanxious being a commonly reported anxiety symptom in children with severe TBI [40]. When comparing children with mild TBI, moderate/

severe TBI and OI, overall results suggests a potential relationship between the degree of neurological insult that has occurred, and the risk of developing new-onset anxiety disorders [38]. In addition, it has been noted that there is a similar link found for those with PTSD following TBI. The research suggests that while there is a rare (yet, noted) occurrence of PTSD following moderate or severe TBI in children, and a statistically significant differ‐ ence in the frequency of this occurrence between children with moderate or severe TBI to children with OI, this relationship may not exist for children with only mild TBI. Further‐ more, the most important predictors for anxiety symptomatology following childhood TBI include social disadvantage/family social status, severity of TBI, psychosocial adversity and younger age of injury [33-35, 37, 40-41].

#### **5.1. Methodological concerns**

As indicated above in Table 2, the studies were analysed according to their methodological merit, as determined by set criteria [31]. Three of the studies [11, 33, 38] included all of the listed criteria, and the most commonly missed criteria was a lack of a control group in 7 out of the 11 papers [32, 34-35, 37, 39-41]. All included studies showed evidence of criteria b), c) and e), indicating the use of longitudinal designs, well-defined TBI groups and standardised outcome measures and assessments. Only one study did not include more than 20 TBI participants or control for pre-injury characteristics [36].

Of concern is the number of studies that did not include a non-TBI group. The research being discussed explores the rate of anxiety disorders following TBI in children and adolescents, and although this information can be obtained using only a TBI group, the strength of the results may be enhanced if authors could compare these rates to a non-injured or OI group of participants, particularly when anxiety is already evident in high rates in the general popula‐ tion. It is also interesting to note that of the studies that did include a control group [11, 33, 36, 38], all utilised an OI group with injuries sustained to regions of the body other than the head or neck. There is therefore an absence of studies that have compared the incidence of anxiety disorders in children and adolescents with TBI and healthy control subjects. While it is useful to use an OI comparison group as this eliminates confounding variables associated with the nature of injury and exposure to hospital/rehabilitation services, the literature is in need of research that compares the incidence of anxiety following TBI to what is expected in the general child population.

In addition, while all but one controlled for pre-injury characteristics and risk factors [36], issues pertain to the validity of such measures regarding the timing of testing. In all cases, premorbid functioning such as behavior scores, pre-existing psychiatric disorders and family functioning assessments were conducted at 'baseline' – meaning that they were assessed following the TBI event. This presents a large issue within the TBI literature as it is difficult to ascertain the validity of reports on child variables that were present before the injury when they are considered retrospectively. Psychological stress as a result of the injury, for both the child and the parent, is likely to affect the ability for the parent or child to recall incidents and functioning before the TBI event. Furthermore, the child's current behavior and functioning may change the child or parent's perspective of what occurred before the TBI. However, the authors do attempt to alleviate the effects of this issue in that testing at 'baseline' was always conducted as soon as possible, once major concussion symptoms (such as PTA) had resided.

A major strength among the literature on anxiety disorders following TBI in children and adolescents is the use of a prospective, longitudinal design with follow-up assessments of behavior and anxiety. Several studies conducted follow-ups up to 1 year after TBI [11, 32-35, 37, 40-41], which allowed for the examination of long-term effects of TBI and the persistence and chronicity of anxiety in such participants. Furthermore, in fewer studies [11, 32-33], participants were assessed at multiple time points, which is essential for exploring the pattern of anxiety disorders and symptomatology following TBI across time. Additionally, welldefined severity groups are important when conducting TBI studies, particularly when comparing groups and when assessing the influence of injury severity on outcomes. Evidently, the studies presented in this paper all assessed and defined severity of TBI using the GCS. The GCS is regarded as the most common method of assessing TBI severity [17], and has been proven both useful and valid in multiple studies. In addition, in many cases other markers of TBI severity were also examined, such as positive CT scans [32-33, 38-39] and the duration of LOC [33, 36-37, 39].

Overall, when considering the methodological merit of the studies listed in this paper, the results seem quite positive. While the absence of a control group for over half of the studies poses some concern for the generalizability of findings, their methodology is strengthened by the use of a longitudinal design with timely follow-up assessments post-TBI and well-defined and accurately assessed TBI severity for each injury group. In addition, all but one study [36] had an adequately sized sample of TBI participants. Furthermore, outcome measures for all of the papers were assessed using standardised, common measures and procedures for examining the presence of anxiety disorders in children and adolescents.

#### **5.2. Other concerns**

severe TBI and OI, overall results suggests a potential relationship between the degree of neurological insult that has occurred, and the risk of developing new-onset anxiety disorders [38]. In addition, it has been noted that there is a similar link found for those with PTSD following TBI. The research suggests that while there is a rare (yet, noted) occurrence of PTSD following moderate or severe TBI in children, and a statistically significant differ‐ ence in the frequency of this occurrence between children with moderate or severe TBI to children with OI, this relationship may not exist for children with only mild TBI. Further‐ more, the most important predictors for anxiety symptomatology following childhood TBI include social disadvantage/family social status, severity of TBI, psychosocial adversity and

As indicated above in Table 2, the studies were analysed according to their methodological merit, as determined by set criteria [31]. Three of the studies [11, 33, 38] included all of the listed criteria, and the most commonly missed criteria was a lack of a control group in 7 out of the 11 papers [32, 34-35, 37, 39-41]. All included studies showed evidence of criteria b), c) and e), indicating the use of longitudinal designs, well-defined TBI groups and standardised outcome measures and assessments. Only one study did not include more than 20 TBI

Of concern is the number of studies that did not include a non-TBI group. The research being discussed explores the rate of anxiety disorders following TBI in children and adolescents, and although this information can be obtained using only a TBI group, the strength of the results may be enhanced if authors could compare these rates to a non-injured or OI group of participants, particularly when anxiety is already evident in high rates in the general popula‐ tion. It is also interesting to note that of the studies that did include a control group [11, 33, 36, 38], all utilised an OI group with injuries sustained to regions of the body other than the head or neck. There is therefore an absence of studies that have compared the incidence of anxiety disorders in children and adolescents with TBI and healthy control subjects. While it is useful to use an OI comparison group as this eliminates confounding variables associated with the nature of injury and exposure to hospital/rehabilitation services, the literature is in need of research that compares the incidence of anxiety following TBI to what is expected in the general

In addition, while all but one controlled for pre-injury characteristics and risk factors [36], issues pertain to the validity of such measures regarding the timing of testing. In all cases, premorbid functioning such as behavior scores, pre-existing psychiatric disorders and family functioning assessments were conducted at 'baseline' – meaning that they were assessed following the TBI event. This presents a large issue within the TBI literature as it is difficult to ascertain the validity of reports on child variables that were present before the injury when they are considered retrospectively. Psychological stress as a result of the injury, for both the child and the parent, is likely to affect the ability for the parent or child to recall incidents and functioning before the TBI event. Furthermore, the child's current behavior and functioning may change the child or parent's perspective of what occurred before the TBI. However, the

younger age of injury [33-35, 37, 40-41].

participants or control for pre-injury characteristics [36].

**5.1. Methodological concerns**

216 A Fresh Look at Anxiety Disorders

child population.

Examining the literature, common methodological concerns arise across the featured studies. An important finding is that there is a lack of research which has included participants with mild TBI, with a large focus on children with severe TBI. Of the studies in this review, five included participants who had suffered mild TBI [11, 32, 36, 38-39], while the majority only included participants with moderate-severe TBI or severe TBI. Considering that studies on externalising disorders have indicated an increased incidence of psychiatric disorders such as ADHD, ODD, CD, drug and alcohol abuse/use and personality disorders in children with even mild TBI [6-7, 9], it surprising that such a sample has been relatively neglected in the literature.

In relation to this, it is often suggested within the PTSD literature that the diagnosis of PTSD following TBI is not valid due to the nature of the psychological events that follow such an injury [32-33, 36]. This argument states that children who suffer from TBI and lose conscious‐ ness or experience PTA are unable to suffer the anxiety of PTSD that is associated with reexperiencing a traumatic event, as the event itself cannot be recalled and subsequently emotionally suppressed [32-33]. The authors, however, do not discuss this argument in relation to children who suffer from a TBI mild enough that it does not result in loss of consciousness (LOC) or PTA. However, instead they tended to utilise samples of children with more severe injuries [33-35], thereby contradicting their argument. Furthermore, over half of the research has focused on solely PTSD following TBI [11, 32-36] and excluded other anxiety disorders, due to the close relationship it has with trauma [40]. Moreover, one study [36] applied more focus on PTSD in children following road traffic accidents, and utilised the TBI group as a control for confounds associated with such an injury, rather than exploring long-term anxiety outcomes following TBI.

Also interesting to note in regards to PTSD following TBI is the discrepancy that is often found between reports of PTSD symptomatology from the child versus the parents. For instance, in [32] and [36], both studies utilised both parent and child report questionnaires to assess PTSD. However, correlational analyses indicated a relatively low relationship between reports from children and adults, and of which the relationship was non-significant in both cases. The meaning of this is not well discussed, which poses a challenge to the methodology of papers which utilise only one source of PTSD symptom reporting. In addition, it is not well-known whether this relationship (or lack thereof) also exists for other anxiety measures. Indeed, some have questioned the validity of parent-report methods for assessing anxiety, arguing that these internal states can be reliably reported by the children themselves, without need for parental reports [38]. Internalising disorders in children and adolescents are not as readily observable for parents, and as such, it may be difficult to report their presence or absence in their children. Further, younger children and children who have sustained a TBI and have developed cognitive deficits may not understand or be able to articulate the internalising problems they are experiencing. As such, this discrepancy between parent and child reports of internalising symptoms should be explored further to examine the best possible way to accurately assess difficulties such children and adolescents may exhibit following TBI.

The importance of gender as a predictor of anxiety disorders following TBI has been signifi‐ cantly neglected within this literature. Considering that a higher number of females experience and report internalising and anxiety problems compared to males in both a normal [48] and TBI [30] population, it is surprising that gender differences in these studies hasn't been thoroughly explored. Women are at greater risk of developing anxiety disorders including GAD, PD and PTSD [49], and also some phobias [50]. However, differences in the psychopa‐ thology of children following TBI is has rarely been compared across gender groups, as is evident in the above samples. Given that much work has been done exploring externalising behavioural outcomes of children post-TBI, such as attention, hyperactivity and aggressive behaviours [3-6], it is important that behaviours that are more likely to be seen in a female population are also as extensively explored.

Finally, while there have been some advancements towards the study of internalising prob‐ lems, including anxiety disorders, following TBI in children and adolescents, it is vital to note that of the 11 papers presented here, 5 of these utilised the same cohort of individuals [34-35, 37, 40-41]. While the sample itself was derived from a large database of referrals from tertiary trauma centres over a relatively large period of time (years 1992-1996), the fact that these studies were replicated among the same cohort limits the generalizability of the results to anxiety and TBI literature. Although the studies provided useful information regarding the relationship between TBI and anxiety disorders [34, 37, 40] and also neural correlates associ‐ ated with anxiety disorders after TBI [35, 41], the literature remains sparse in relation to different cohorts of children and adolescents being examined for such variables.

### **5.3. Practical implications**

injuries [33-35], thereby contradicting their argument. Furthermore, over half of the research has focused on solely PTSD following TBI [11, 32-36] and excluded other anxiety disorders, due to the close relationship it has with trauma [40]. Moreover, one study [36] applied more focus on PTSD in children following road traffic accidents, and utilised the TBI group as a control for confounds associated with such an injury, rather than exploring long-term anxiety

Also interesting to note in regards to PTSD following TBI is the discrepancy that is often found between reports of PTSD symptomatology from the child versus the parents. For instance, in [32] and [36], both studies utilised both parent and child report questionnaires to assess PTSD. However, correlational analyses indicated a relatively low relationship between reports from children and adults, and of which the relationship was non-significant in both cases. The meaning of this is not well discussed, which poses a challenge to the methodology of papers which utilise only one source of PTSD symptom reporting. In addition, it is not well-known whether this relationship (or lack thereof) also exists for other anxiety measures. Indeed, some have questioned the validity of parent-report methods for assessing anxiety, arguing that these internal states can be reliably reported by the children themselves, without need for parental reports [38]. Internalising disorders in children and adolescents are not as readily observable for parents, and as such, it may be difficult to report their presence or absence in their children. Further, younger children and children who have sustained a TBI and have developed cognitive deficits may not understand or be able to articulate the internalising problems they are experiencing. As such, this discrepancy between parent and child reports of internalising symptoms should be explored further to examine the best possible way to accurately assess

The importance of gender as a predictor of anxiety disorders following TBI has been signifi‐ cantly neglected within this literature. Considering that a higher number of females experience and report internalising and anxiety problems compared to males in both a normal [48] and TBI [30] population, it is surprising that gender differences in these studies hasn't been thoroughly explored. Women are at greater risk of developing anxiety disorders including GAD, PD and PTSD [49], and also some phobias [50]. However, differences in the psychopa‐ thology of children following TBI is has rarely been compared across gender groups, as is evident in the above samples. Given that much work has been done exploring externalising behavioural outcomes of children post-TBI, such as attention, hyperactivity and aggressive behaviours [3-6], it is important that behaviours that are more likely to be seen in a female

Finally, while there have been some advancements towards the study of internalising prob‐ lems, including anxiety disorders, following TBI in children and adolescents, it is vital to note that of the 11 papers presented here, 5 of these utilised the same cohort of individuals [34-35, 37, 40-41]. While the sample itself was derived from a large database of referrals from tertiary trauma centres over a relatively large period of time (years 1992-1996), the fact that these studies were replicated among the same cohort limits the generalizability of the results to anxiety and TBI literature. Although the studies provided useful information regarding the relationship between TBI and anxiety disorders [34, 37, 40] and also neural correlates associ‐

difficulties such children and adolescents may exhibit following TBI.

population are also as extensively explored.

outcomes following TBI.

218 A Fresh Look at Anxiety Disorders

Given the findings in the literature, when assessing children who have been admitted for TBI, it may be important to screen for factors associated with family psychiatric history of inter‐ nalising disorders, the individual's past psychiatric history of internalising disorders, and also to examine levels of psychosocial adversity. Furthermore, the increased vulnerability of children with a younger age at injury to developing subsequent anxiety disorders would be considered in such assessments. Children who are younger at the time of TBI, have greater psychosocial adversity and have some history of psychiatric internalising disorders may be at greater risk of developing anxiety disorders, and so if such children are targeted early, appropriate intervention practices may be put in place.

Intervention programs for children vulnerable to developing anxiety disorders following TBI may include relaxation procedures for the parent and the child, coping strategies, self-esteem building activities, or open communication between the parent and child regarding the child's anxiety symptoms or worries. Furthermore, those at high risk of developing anxiety disorders may benefit from a follow-up screen following their TBI to assess for any anxiety symptoms, and potentially undergo typical anxiety management procedures such as cognitive-behavior therapy, behavioural assessment and psychotherapy. It is important that such poor outcomes following TBI are targeted and managed early, to enhance quality of life and prevent the negative effects anxiety would have on both social and academic learning and development.

### **5.4. Limitations**

One major limitation of this review is that only 11 papers have been reviewed for discussion. In addition, among these papers, 5 utilised the same cohort of participants. However, this fact highlights further the need for more work in the field of anxiety disorders following childhood TBI. As mentioned above, it is likely that there is less of a focus on internalising behaviours because males have been reported to be at greater risk of TBI than females [28-29], and that the more overt and distressing nature of externalising problems [27] are more readily reported by parents, and also more observable to the human eye.

#### **5.5. Future directions and conclusions**

It is clear from the small number of studies generated in this literature search that much work needs to be done in examining the incidence and rate of anxiety disorders following TBI in children and adolescents. Studies that have investigated the presence and rate of PTSD diagnoses and symptomatology [34], and the rate of pre- and post-TBI anxiety disorders and symptoms [40], should be replicated in different samples, with the inclusion of children with both mild and moderate TBI. Moreover, future studies should include the use of control groups to compare against children with TBI, and utilise both healthy control participants and children with OI, as the presence and rate of anxiety disorders is expected to be different among each of these groups. Furthermore, the relationship between parent and child reports of anxiety disorders should be examined, considering the low correlation scores found among reports of PTSD in the present literature [33, 36]. Finally, more studies should attempt to explore brain regions and lesion burdens associated with anxiety disorders in such a sample, as such studies are severely lacking.

This chapter examined the current literature assessing the presence of anxiety disorders following TBI in children and adolescents. While the literature to date is sparse, it may be concluded that children who have suffered from a TBI (mild, moderate or severe), are at a higher risk of developing subsequent anxiety disorders, even 1 year following the injury event. Moreover, children with more severe injuries, greater psychosocial adversity, and younger age at injury may be at the greatest risk, and are a group who would benefit from early intervention. Further studies are needed to replicate all the above findings and generate a more comprehensive view of the relationship between TBI and internalising disorders within the literature.

### **Author details**

Michelle Albicini1\* and Audrey McKinlay2

\*Address all correspondence to: michelle.albicini@monash.edu

1 Monash University; School of Psychological Sciences, Australia

2 The University of Melbourne, School of Psychological Sciences, Psychology Clinic, Aus‐ tralia

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of these groups. Furthermore, the relationship between parent and child reports of anxiety disorders should be examined, considering the low correlation scores found among reports of PTSD in the present literature [33, 36]. Finally, more studies should attempt to explore brain regions and lesion burdens associated with anxiety disorders in such a sample, as such studies

This chapter examined the current literature assessing the presence of anxiety disorders following TBI in children and adolescents. While the literature to date is sparse, it may be concluded that children who have suffered from a TBI (mild, moderate or severe), are at a higher risk of developing subsequent anxiety disorders, even 1 year following the injury event. Moreover, children with more severe injuries, greater psychosocial adversity, and younger age at injury may be at the greatest risk, and are a group who would benefit from early intervention. Further studies are needed to replicate all the above findings and generate a more comprehensive view of the relationship between TBI and internalising disorders within the

2 The University of Melbourne, School of Psychological Sciences, Psychology Clinic, Aus‐

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**Author details**

Michelle Albicini1\* and Audrey McKinlay2

\*Address all correspondence to: michelle.albicini@monash.edu

1 Monash University; School of Psychological Sciences, Australia


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