Veterans often present with a co-morbid symptom presentation, and co-morbid symptom expression has demonstrated poorer treatment outcomes across psychopathologies [14,15]. The co-morbidities of chronically depressed individuals include anxiety disorders and substance dependence, somatic and physiological disorders and include a range of personality disorders [16,17]. Understanding how these various symptom structures and clinical presentations relate, and developing effective strategies for addressing clinical concerns is paramount, if we hope to effectively treat patients with co-morbid depression and PTSD.

We are focusing on the co-occurrence of chronic depression and chronic posttraumatic stress disorder (PTSD), because it represents the most common co-occurring symptom set for males (48%) and females (49%) of any Axis I disorders, with the exception of PTSD and alcohol abuse for males (51%) [18]. This co-morbidity has also become increasingly critical to our understanding of the etiology of chronic depression from a developmental perspective. For the patient presenting with early onset chronic depression we can typically find a developmental profile of maltreatment in the form of emotional abuse or neglect, physical abuse or neglect, and sexual abuse [19]. However, interpersonal maltreatment is not the only childhood traumatic experience occurring within the context of family and caregiver relationships, individuals are also subject to a range of losses or "psychological insults" [20], such as warfare, sociopolitical stressors, and environmental disasters. These stressors often have a negative impact on individuals' views of themselves, others, and their world [20].

The foundational derailment of secure attachments and normative cognitive-affective development produces negative self-other attributions and an enhanced fear response toward unfamiliar or threatening environmental stimuli. Behaviorally, this is manifested in a predominantly avoidant coping strategy, which, in turn, increases the strength of the fear structure [21]. Chronic depressive trajectories of late onset or adult traumatic events have received less attention in the literature and yet represent approximately 8% of the chronically depressed adult population. For instance, over 50% of military veterans diagnosed with PTSD carry a diagnosis of depression lasting for two or more years with no evidence of depressive disorder prior to their military duty [22,9]. This co-morbid PTSD/chronically depressed population has a high treatment refractory rate for both antidepressant medication and psychosocial interventions [23].

270 Psychiatric Disorders – New Frontiers in Affective Disorders

treatment resistant population.

**2. Problem statement**

**2.1. Co-morbid MDD and PTSD**

effective than groups that were culturally nonspecific.

System where we have treated combat veterans, the provision of. Group psychotherapy

The rationale for developing a group format for this established, evidence-based treatment for chronic depression stems, in part, from the need for greater access to treatment for increasingly numbers of veterans returning from combat with PTSD and MDD symptoms. Group methodologies have been shown to be very effective in working with homogeneous populations, both in terms of cultural characteristics and symptom presentation [10]. In fact, veterans share a distinct military culture and as such report a "bond" and increased sense of cohesion with the experiences of each other than they do with most civilians [11]. Utilizing this commonality to enhance a sense of social connection and support as well as counteract patterns of interpersonal avoidance may improve treatment outcomes for this frequently

In a meta-analysis of 48 group therapy studies of depression treatment, McDermut, Miller, Brown [12] found that patients treated in group modalities reported a significant reduction in depressive symptoms when compared to 85% of untreated patients. In studies exploring the benefits of culturally relevant intervention strategies, Ginder and Smith [13] found that when group interventions with homogeneous cultural groups, they were four times more

Veterans often present with a co-morbid symptom presentation, and co-morbid symptom expression has demonstrated poorer treatment outcomes across psychopathologies [14,15]. The co-morbidities of chronically depressed individuals include anxiety disorders and substance dependence, somatic and physiological disorders and include a range of personality disorders [16,17]. Understanding how these various symptom structures and clinical presentations relate, and developing effective strategies for addressing clinical concerns is paramount, if we hope to effectively treat patients with co-morbid depression and PTSD.

We are focusing on the co-occurrence of chronic depression and chronic posttraumatic stress disorder (PTSD), because it represents the most common co-occurring symptom set for males (48%) and females (49%) of any Axis I disorders, with the exception of PTSD and alcohol abuse for males (51%) [18]. This co-morbidity has also become increasingly critical to our understanding of the etiology of chronic depression from a developmental perspective. For the patient presenting with early onset chronic depression we can typically find a developmental profile of maltreatment in the form of emotional abuse or neglect, physical abuse or neglect, and sexual abuse [19]. However, interpersonal maltreatment is not the only childhood traumatic experience occurring within the context of family and caregiver relationships, individuals are also subject to a range of losses or "psychological insults" [20], such as warfare, sociopolitical stressors, and environmental disasters. These stressors often have a negative impact on individuals' views of themselves, others, and their world [20].

allows greater access to treatment for growing numbers of veterans seeking help.

PTSD is a chronic often disabling disorder that affects approximately 6.8% of the U.S. population with a lifetime prevalence of 3.6% for males, and 9.7% for females [18]. In the Veterans Health Study [22] it was shown that 31% of the over 2,000 veterans sampled, had experienced significant depressive symptoms with 54% of these depressed veterans evidencing one or more psychiatric co-morbidity, predominantly PTSD. Additionally, 88% had medical co-morbidities such as hypertension, heart disease, diabetes, and degenerative joint disease. The lifetime prevalence of Major Depressive Disorder in patient populations such as combat veterans who have a diagnosis of PTSD has been reported to be as high as 68%[24]. Large community sample co-morbidity research has demonstrated that individuals who have PTSD are 3-5 times more likely to develop Major Depressive Disorder over their lifetime [18]. There is a complex interaction among neurobiological and psychosocial factors that involve the overactivation of the hypothalamic-pituitary-adrenal axis [25]. While the empirical literature has begun to outline the interaction of these two disorders, most of the treatment literature focuses on effective interventions with either MDD or PTSD alone. This presents a gap in our understanding about how to treat patients with co-morbid chronic depression/PTSD.

That we are treating interacting disorders rather than two separate or sequential disorders complicates both treatment and the evidence base of the treatment modality, which is based on data from single diagnosis samples. Regarding the complexity of treatment, the clinician has, in the case of PTSD, the treatment goal of reducing patients' trauma symptoms when their motivation is poor and their coping strategies (i.e., avoidance, substance abuse, anger) are maladaptive and entrenched. When treatment for chronic depression is linked to that of PTSD, treatment can be compromised and derailed by the expression of trauma symptoms that may undermine the patient's sense of safety and trust and reduce treatment adherence.

As clinicians working in the Veterans Administration HealthCare System, we have noted that when these disorders co-occur, patients report greater symptom distress, treatment interventions can become highly problematic, and/or patients become treatment refractory [23]. Although first-line PTSD treatments, such as Prolonged Exposure Therapy (PE) and Cognitive Processing Therapy (CPT) for non-comorbid PTSD report a remission of acute depressive symptoms when PTSD symptoms are actively addressed, some chronically depressed patients find it difficult to engage in and complete trauma focused therapies that activate traumatic memories and require adherence to between-session imaginal and in-vivo exposures. This problem may be reflected in a 23% drop-out rate for civilians receiving trauma-focused therapy and as high as 30% dropout for veterans with PTSD. Many of these veterans had co-occurring disorders, including MDD [24].

Group Intervention for Chronic Depression and PTSD 273

Development of narrative (beginning, mid, end points, behavioral focus)

Remediation of interpretations and development of Action Interpretations

Introduction of Behavioral Activation - Daily monitoring sheet and identification of

Continued review of Situational Analyses, and Future Situational Analyses with focus on

Role plays to practice new interpersonal behaviors generated in group, i.e., *"let's try*

Identification of interpersonal "hot spots" related to Significant Other History

Link behaviors to circumplex – role play alternative behaviors, and cognitions that

Focus on behavioral manifestation of *transference hypothesis* in interpersonal life.

Improving behavioral skills, i.e., behavioral activation, communication,

Complete Interpersonal Discrimination Exercise (IDE) based on Situational

Identify situational interpretations or "reads"

Actual Outcome=Desired Outcome

depressant vs. antidepressant behaviors

**3.5. Sessions 6-10 early treatment**

Active listening/communication skills

Monitoring and incremental increase antidepressant activities

Situational Analyses and Future Situational Analyses with focus on:

Review the impact of behaviors on achieving Desired Outcomes

Situational Analyses and Future Situational Analyses with focus on:

Generalization and consolidation of new learning

developing new behavioral skills.

Emotion Regulation skills

*that out and see how it works"*

**3.6. Session 10-12 mid- treatment**

Interpersonal Impact Inventory (IMI)

mediate interpersonal "pulls."

**3.7. Session 12-18 mid-treatment**

**3.8. Session 18-24 late treatment**

CBASP skills are being practiced weekly:

Analyses

*transference hypothesis* for each group member.

assertiveness, emotion regulation

Assertiveness

Generalization of learning

## **3. Application area**

## **3.1. CBASP group application**

The adaption of CBASP to a group treatment maintains the core structure and principles of the individual treatment while expanding on behavioral skill development and behavioral activation. The structure of the CBASP group follows the outline provided below, which provides for pretreatment screening and education, treatment measures and co-construction of the *transference hypothesis*, which is generalized to the impact on the group environment rather than specifically on the therapist as in individual CBASP treatment.

## **3.2. Pre-treatment interview**

Screening and Baseline measures

## **3.3. Session structure**

\*Each member is responsible for 3 CQs each week.

## **3.4. Session 1-6 initial phase**

Primary focus is on the development of Situational Analysis using the Coping Questionnaire:

Situational "slice of time"

Introduction of Behavioral Activation - Daily monitoring sheet and identification of depressant vs. antidepressant behaviors

## **3.5. Sessions 6-10 early treatment**

Continued review of Situational Analyses, and Future Situational Analyses with focus on developing new behavioral skills.

272 Psychiatric Disorders – New Frontiers in Affective Disorders

**3. Application area**

**3.1. CBASP group application**

**3.2. Pre-treatment interview**

Screening and Baseline measures

Beck Depression Inventory -II

Depression Timeline

**3.3. Session structure**

Interview and differential diagnosis MINI v6,

CBASP Interpersonal Questionnaire (CIQ)

 Interpersonal Impact Inventory (IMI) Interpersonal Inventory of Problems (IIP)

Assignment and troubleshooting

**3.4. Session 1-6 initial phase**

Situational "slice of time"

\*Each member is responsible for 3 CQs each week.

Significant Other History (SOH), *Transference Hypothesis*

 Check-in (mood and activity level) 10 minutes Presentation of Coping Questionnaire \* 50 minutes New learning, i.e., behavioral skills, 20 minutes Consolidation of new learning 10 minutes

veterans had co-occurring disorders, including MDD [24].

Cognitive Processing Therapy (CPT) for non-comorbid PTSD report a remission of acute depressive symptoms when PTSD symptoms are actively addressed, some chronically depressed patients find it difficult to engage in and complete trauma focused therapies that activate traumatic memories and require adherence to between-session imaginal and in-vivo exposures. This problem may be reflected in a 23% drop-out rate for civilians receiving trauma-focused therapy and as high as 30% dropout for veterans with PTSD. Many of these

The adaption of CBASP to a group treatment maintains the core structure and principles of the individual treatment while expanding on behavioral skill development and behavioral activation. The structure of the CBASP group follows the outline provided below, which provides for pretreatment screening and education, treatment measures and co-construction of the *transference hypothesis*, which is generalized to the impact on the group environment

Primary focus is on the development of Situational Analysis using the Coping Questionnaire:

rather than specifically on the therapist as in individual CBASP treatment.

## **3.6. Session 10-12 mid- treatment**

Situational Analyses and Future Situational Analyses with focus on:

### **3.7. Session 12-18 mid-treatment**

Situational Analyses and Future Situational Analyses with focus on:

#### **3.8. Session 18-24 late treatment**

CBASP skills are being practiced weekly:

Group Intervention for Chronic Depression and PTSD 275

CBASP TAU

BDI-II PCL-C

Note: CBASP group N=52 and TAU group N=45. BDI=Beck Depression Inventory–II, PCL-C= PTSD Checklist-Civilian.

BDI pre BDI post PCL pre PCL post

Figure 2 CBASP session scores on BDI-II and PCL-C with 1 and 6 months follow up.

Pre Post 1 mon 6mon

The conclusions drawn from this sample of male veterans with chronic depressive disorders and co-morbid PTSD, demonstrates the feasibility of CBASP as a treatment for co-morbid MDD/PTSD with significant reductions in depression and PTSD symptoms compared to treatment as usual. The lack of randomization, absence of a control condition, and a relatively small effect size represent some of the limitations in this study. Nevertheless, the results suggest that using group CBASP to address co-morbid chronic

**Figure 1.** CBASP and TAU Pre and Post scores on BDI-II and PCL-C

**Figure 2.** CBASP mean scores on BDI-II and PCL-C (N=52)

**5. Limitations and future research**

0

10

20

30

40

50

60

Interpersonal Discrimination Exercise based on situational "hotspots"

## **3.9. Sessions 24-28 termination and relapse prevention**

## **4. Research course**

## **4.1. Method**

In a study conducted at the Ann Arbor Veterans Healthcare System, 52 male veterans, aged 55-66 with PTSD and MDD were treated using CBASP group therapy for 28 weeks [26]. A comparative sample of 45 male veterans, aged 49-62, were treated with a supportive therapy for the same number of sessions. There was exclusion criteria for psychosis/schizophrenia, bipolar disorder, and active substance abuse. In each of these group therapy conditions, chronic depression was the primary diagnosis, PTSD was secondary. All participants were on antidepressant medications and dosage was unchanged during the group intervention. Symptom measurement, using the BDI-II [27] and the PSTD Checklist-C [28] were given to all therapy participants at the beginning and end of treatment. These measures were again given at 1 month and 6 month followup.

## **4.2. Research results**

Data was collected and analyzed using SPSS version 18. Group data was compared using paired t-test. There was a significant improvement in the CBASP group*, t* (51) = 5.12, *p*< .004 for depression and PTSD symptoms *t* (51) =3.24*, p<.05*, as compared to no significant change in the supportive treatment group *t* (44) = 1.15, *ns* (Figure 1).

The CBASP group was measured at the end of 1 month post treatment and again after 6 months post treatment to assertain the durability of the effects of treatment. The results of the treatment sessions and follow up measures on the BDI-II and PCL-C are seen in Figure 2. Depression symptoms demonstrated increase at 1 month and 6 month follow–up assessment compared to end of treatment level. The PCL-C continued to drop at 1 month and then showed a increase at 6 months. The increase for both the BDI-II and PCL-C during the follow up phase were that was nonsignificant.

Note: CBASP group N=52 and TAU group N=45. BDI=Beck Depression Inventory–II, PCL-C= PTSD Checklist-Civilian. **Figure 1.** CBASP and TAU Pre and Post scores on BDI-II and PCL-C

**Figure 2.** CBASP mean scores on BDI-II and PCL-C (N=52)

Figure 2 CBASP session scores on BDI-II and PCL-C with 1 and 6 months follow up.

## **5. Limitations and future research**

274 Psychiatric Disorders – New Frontiers in Affective Disorders

Listening, Assertiveness, Emotion regulation

**3.9. Sessions 24-28 termination and relapse prevention**

Establish future meeting dates and support contacts

in the supportive treatment group *t* (44) = 1.15, *ns* (Figure 1).

the follow up phase were that was nonsignificant.

Interpersonal interactions and behavioral skills: Behavioral Activation, Active

 Review of basic principles of learning theory and the issues related to extinction trial Individualized behavioral practice plan, identification of roadblocks, supports, and

In a study conducted at the Ann Arbor Veterans Healthcare System, 52 male veterans, aged 55-66 with PTSD and MDD were treated using CBASP group therapy for 28 weeks [26]. A comparative sample of 45 male veterans, aged 49-62, were treated with a supportive therapy for the same number of sessions. There was exclusion criteria for psychosis/schizophrenia, bipolar disorder, and active substance abuse. In each of these group therapy conditions, chronic depression was the primary diagnosis, PTSD was secondary. All participants were on antidepressant medications and dosage was unchanged during the group intervention. Symptom measurement, using the BDI-II [27] and the PSTD Checklist-C [28] were given to all therapy participants at the beginning and end of treatment. These measures were again given at 1 month and 6 month follow-

Data was collected and analyzed using SPSS version 18. Group data was compared using paired t-test. There was a significant improvement in the CBASP group*, t* (51) = 5.12, *p*< .004 for depression and PTSD symptoms *t* (51) =3.24*, p<.05*, as compared to no significant change

The CBASP group was measured at the end of 1 month post treatment and again after 6 months post treatment to assertain the durability of the effects of treatment. The results of the treatment sessions and follow up measures on the BDI-II and PCL-C are seen in Figure 2. Depression symptoms demonstrated increase at 1 month and 6 month follow–up assessment compared to end of treatment level. The PCL-C continued to drop at 1 month and then showed a increase at 6 months. The increase for both the BDI-II and PCL-C during

Group feedback of individual gains, areas of vulnerability, and role in the group

Interpersonal Discrimination Exercise based on situational "hotspots"

Situational Analysis and Future SAs

contacts

**4.1. Method**

up.

**4. Research course**

**4.2. Research results**

The conclusions drawn from this sample of male veterans with chronic depressive disorders and co-morbid PTSD, demonstrates the feasibility of CBASP as a treatment for co-morbid MDD/PTSD with significant reductions in depression and PTSD symptoms compared to treatment as usual. The lack of randomization, absence of a control condition, and a relatively small effect size represent some of the limitations in this study. Nevertheless, the results suggest that using group CBASP to address co-morbid chronic

depression and PTSD provides a feasible means of addressing the complexities of these cooccurring disorders.

Group Intervention for Chronic Depression and PTSD 277

[2] McCullough, J.P., Jr., Lord, B.D., Conley, K.A. & Martin, A.M. (2010). A method for conducting intensive psychological studies with early-onset chronically depressed

[3] McCullough, J. P. Jr. & Penberthy, J.K. (2011). Cognitive Behavioral Analysis System of Psychotherapy for chronic depression. In Springer, W.W., Allen, R. & Beevers, C.G. (Eds.). *Treatment of Depression in Adolescents and Adults: Clinician's Guide to Evidence-*

[4] Wiersma, J.E., Van Schaik, DJF, van Oppen, P., McCullough, Jr., J.P, Schoever, R.A., Dekker, J.J. et al. (2008). Treatment of chronically depressed patients: A multisite randomized controlled trial testing the effectiveness of CBASP for chronic depressions

[5] Blalock, J.A., Fouladi, R.T., Cinciripini, P.M., Markowitz, C., Klein, .N., Rothbaum, .O., Arnow, B.A., Manber, R., Riso, L.P., Sui, D., McCullough, Jr., J.P. *(April, 2008)*. Cognitive and behavioral mediators of combined pharmacotherapy and psychotherapy of chronic

[6] Klein, D.N., Schwartz, J.E., Santiago, N.J., Vivian, D., Vocisano, C., Castonguay, L.G., Arnow, B.A., Blalock, J.A., Markowitz, J.C., Rothbaum, B.O., & McCullough, Jr. J.P. (2003). Therapeutic alliance in depression treatment: Controlling for prior change and

[9] Hoge, C.W., Auchterlonie, J.L., Milliken, C.S.(2006). Mental health problems, use of mental health services, and attrition from military service after returning from

[10] Sue, S., Zane, N. (2009). The role of culture and cultural techniques in psychotherapy: A

[11] Reger, M.A., Etherage, J. R., Reger, G.M.,Gahm, G.A (2008).Civilian Psychologists in an Army Culture: The Ethical Challenge of Cultural Competence. Military Psychology

[12] McDermut, W., Miller, I.W., Brown, R.A. (2001). The Efficacy of Group Psychotherapy for Depression: A Meta-analysis and Review of the Empirical Research. *Clinical*

[13] Griner, D., Smith, T.B. (2006). Culturally adapted mental health intervention: A metaanalytic review. *Psychotherapy: Theory, Research, Practice, Training*, 43, 531-548. [14] Keitner, G.I., Ryan, C.E., Miller, I.W., Kohn, R. & Epstein, N.B. (1991). Twelve month outcomes of patients with major depression and comorbid psychiatric or medical illness

critique and reformulation. *Asian American Journal of Psychology*, 1, 3-14.

patient characteristics. *Journal of Consulting and Clinical Psychology, 71*, 997-1006. [7] Nemeroff, C.B., Heim, C.M., Thase, M.E., Klein, D.N., Rush, A.J., Schatzberg, A.F., Ninan, P.T., McCullough, J.P., Weiss, P., Dunner, D.L., Rothbaum, B.O., Kornstein, S.G., Keitner, G., & Keller, M.B. (2003). Differential responses to psychotherapy versus pharmacotherapy in the treatment of patients with chronic forms of major depression and childhood trauma. Proceedings of the National Academy of Sciences, 100, 14293-14296. [8] Santiago, NJ, Klein, DN, Vivian, D, Arnow, BA, Blalock,JA, Kocsis, JH, Markowitz, JC, Manber, R, Riso, LP, Rothbaum, BO, Rush, AJ, Thase, ME, McCullough. JP, Jr. (2005). The therapeutic alliance and CBASP-specific skill acquisition in the treatment of chronic

patients. *American Journal of Psychotherapy, 64*, 317-338.

depression. *Cognitive Therapy and Research, 32*, 197-211.

depression. *Cognitive Therapy and Research, 29,* 803–817.

deployment to iraq or afghanistan. *JAMA*, 295, 9, 1023-1032.

Special Issue: Clinical Military Psychology Ethics. 20, (1), 21-35.

(chronic depression). *American Journal of Psychiatry*, 148, 345-350.

*Psychology: Science and Practice,* 8, 98–116.

*Based Practice*. Hoboken, NJ: Wiley & Sons. Chapter 5, pp. 183-220.

versus usual secondary care. *Biological Medical Central Psychiatry*, *8*, 1-13.

The direction of future research is focused on dismantling of the CBASP method to identify the relative power of the active mechanisms within the model as well as their interrelationship and impact on outcome. In addition, we are actively exploring different configurations and dosages of the group method to determine the most effective delivery system. This includes explore the added benefit of parallel individual CBASP sessions as well as providing twice weekly group sessions to see if these agumentations provide significant additive effects to weekly, group only sessions. We believe that it is essential to provide termination phase sessions that are paced to the patients' learning aquisition and consolidation. This may necessiate spread out session at the end of group treatment, with the expectation that this might minimize the extinction effect and symptom relapse.

## **6. Conclusions**

CBASP group therapy shows promise in the facilitation of cognitive, emotional, and behavioral change by providing the opportunity for patients to process reactions with other group members who share similar life experiences. Pilot studies have shown CBASP to be feasible and effective in a group format [29] whether alone or in combination with individual therapy. In this chapter we have focused on culturally specific application for group CBASP to treat outpatients in US Veteran Administration Medical Centers; however, CBASP group is being studied in heterogeneous groups and inpatient applications in Canada, Germany the U.S. and UK. Data from this research will serve to inform clinicians as to relative effectiveness of this methodology within a group context, but will begin to address questions about CBASP's therapeutic mechanisms and their role in promoting reduction in the symptoms of chronic depression. Beyond the potential advantages of CBASP groups in terms of greater treatment access and cost-effectiveness, there are the nonspecific factors such as enhanced social support, normalization of symptoms, and interpersonal skill development within a social context that make it a powerful foundation for behavioral change and a durable impediment to depression relapse.

## **Author details**

Todd K. Favorite and Kayla J. Conrad *University of Michigan, Dept. of Psychiatry, Ann Arbor VA Healthcare System, Michigan USA*

## **7. References**

[1] Schramm, E., Zobel, I., Dykierek, P., Kech, S., Brakemeier, E-L., Külz, A., Berger, M. (2011). Cognitive behavioral analysis system of psychotherapy versus interpersonal psychotherapy for early-onset chronic depression: A randomized pilot study. *Journal of Affective Disorders, 129,* 109-116.

[2] McCullough, J.P., Jr., Lord, B.D., Conley, K.A. & Martin, A.M. (2010). A method for conducting intensive psychological studies with early-onset chronically depressed patients. *American Journal of Psychotherapy, 64*, 317-338.

276 Psychiatric Disorders – New Frontiers in Affective Disorders

occurring disorders.

**6. Conclusions**

**Author details**

**7. References**

Todd K. Favorite and Kayla J. Conrad

*Affective Disorders, 129,* 109-116.

depression and PTSD provides a feasible means of addressing the complexities of these co-

The direction of future research is focused on dismantling of the CBASP method to identify the relative power of the active mechanisms within the model as well as their interrelationship and impact on outcome. In addition, we are actively exploring different configurations and dosages of the group method to determine the most effective delivery system. This includes explore the added benefit of parallel individual CBASP sessions as well as providing twice weekly group sessions to see if these agumentations provide significant additive effects to weekly, group only sessions. We believe that it is essential to provide termination phase sessions that are paced to the patients' learning aquisition and consolidation. This may necessiate spread out session at the end of group treatment, with

the expectation that this might minimize the extinction effect and symptom relapse.

for behavioral change and a durable impediment to depression relapse.

*University of Michigan, Dept. of Psychiatry, Ann Arbor VA Healthcare System, Michigan USA*

[1] Schramm, E., Zobel, I., Dykierek, P., Kech, S., Brakemeier, E-L., Külz, A., Berger, M. (2011). Cognitive behavioral analysis system of psychotherapy versus interpersonal psychotherapy for early-onset chronic depression: A randomized pilot study. *Journal of*

CBASP group therapy shows promise in the facilitation of cognitive, emotional, and behavioral change by providing the opportunity for patients to process reactions with other group members who share similar life experiences. Pilot studies have shown CBASP to be feasible and effective in a group format [29] whether alone or in combination with individual therapy. In this chapter we have focused on culturally specific application for group CBASP to treat outpatients in US Veteran Administration Medical Centers; however, CBASP group is being studied in heterogeneous groups and inpatient applications in Canada, Germany the U.S. and UK. Data from this research will serve to inform clinicians as to relative effectiveness of this methodology within a group context, but will begin to address questions about CBASP's therapeutic mechanisms and their role in promoting reduction in the symptoms of chronic depression. Beyond the potential advantages of CBASP groups in terms of greater treatment access and cost-effectiveness, there are the nonspecific factors such as enhanced social support, normalization of symptoms, and interpersonal skill development within a social context that make it a powerful foundation

	- [15] Rohde, P., Lewinsohn, P.M., & Seeley, J.R. (1991). Comorbidity of unipolar depression: II. Comorbidity with other mental health disorders in adolescents and adults. *Journal of Abnormal Psychology*, 100, 214-222.

**Chapter 13**

© 2013 Seldenrijk et al., licensee InTech. This is an open access chapter 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.

© 2013 Seldenrijk et al., licensee InTech. This is a paper 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.

**Depression, Vascular Conditions and Chronicity**

In recent years, the association between depression and cardiovascular disease has been studied extensively (Nicholson *et al.* 2006; Van der Kooy *et al.* 2007). Cardiovascular disease (CVD) refers to those conditions that affect the heart and blood vessels, including amongst others coronary heart disease, cerebrovascular disease, and peripheral artery disease. According to the World Health Organisation, cardiovascular disease now is the primary cause of death around the world. Depressive disorders enhance the development of CVD by both behavioural and biological pathways. They may contribute to unhealthy lifestyle habits that increase cardiovascular risk, such as smoking, low physical activity, and unhealthy diet. Also, this psychiatric condition is associated with activation of the immune system, blood coagulation, hyperactivity of the physiological stress system (e.g. hypothalamic pituitary adrenal axis), and other biological mechanisms which are thought to be involved in de development and progression of CVD. As these behavioural and biological factors are more continuously present in persons with chronic depression, it can be assumed that the risk of developing CVD is even higher in chronically depressed subjects, although this has not been clearly demonstrated yet. The first aim of this Chapter is to summarize what is known about the association between depression and vascular conditions. An overview of the literature will be given and a more detailed description of recent findings from a large Dutch cohort study on depression and anxiety (Seldenrijk *et al.* 2010; Seldenrijk *et al.* 2011b; Vogelzangs *et al.* 2010) will be presented. The second aim is to discuss the relevance of reviewed findings

Adrie Seldenrijk, Nicole Vogelzangs, Patricia van Oppen,

Brenda Penninx and Anneke van Schaik

http://dx.doi.org/10.5772/51623

**1. Introduction**

for chronic depression.

**2. Depression and vascular comorbidity**

**2.1. Existing evidence on association between depression and CVD**

A recent meta-analysis (Nicholson *et al.* 2006) has reviewed prospective cohort studies that reported on the association between depression and coronary outcomes in healthy

Additional information is available at the end of the chapter

## **Depression, Vascular Conditions and Chronicity**

Adrie Seldenrijk, Nicole Vogelzangs, Patricia van Oppen, Brenda Penninx and Anneke van Schaik

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51623

## **1. Introduction**

278 Psychiatric Disorders – New Frontiers in Affective Disorders

*Abnormal Psychology*, 100, 214-222.

[15] Rohde, P., Lewinsohn, P.M., & Seeley, J.R. (1991). Comorbidity of unipolar depression: II. Comorbidity with other mental health disorders in adolescents and adults. *Journal of*

[16] Kaye, A.L., McCullough, J.P., Roberts, W.C., McCune, K.J., Hamptom, C., & Kornstein, S.G. (1994). Differentiating affective and characterological DSM-III-R psychopathology

[17] McCullough, J.P. (1996). The importance of diagnosing comorbid personality disorder with patients who are chronically depressed. *Depressive Disorders: Index and Reviews*, 1 (1), 16-17. [18] Kessler, R.C, Sonnega, A., Bromet, E., Hughes, M., Nelson,C.B.(1995). Posttraumatic Stress Disorder in the National Comorbidity Survey, *Arch Gen Psychiatry.* 52(12):1048-1060. [19] Cicchetti,D., & Barnett, D. (1991). Attachment organization in maltreatment pre-

[20] Bonnano, Brewin, Kaniasty, & La Greca (2010). Weighing the Costs of Disaster: Consequences, Risks, and Resilience in Individuals, Families, and Communities

[21] Foa, E.B., & Rothbaum, B.O. (1998). Treating the trauma of rape: Cognitive-Behavioral

[22] Valenstein M, Austin K, Khanuja K, McCarthy JF, Owen RE, Blow FC. (2004). Specialty Care for Veterans with Depression in the VHA: 2002 National Registry for Depression (NARDEP) Report. Serious Mental Illness Treatment Research and Evaluation Center. [23] Chermack ST, Zivin K, Valenstein M, Ilgen M, Austin KL, Wryobeck J, Blow FC. (2008). The Prevalence and Predictors of Mental Health Treatment Services in a National

[24] Rauch, S., Favorite, T., Giardino, N., Porcari, C., Martis, B., Liberzon, I. (2009). Relationship between anxiety, depression, and health satisfaction among veterans with

[25] Yehuda, R., Giller, E.L., Southwick, S.M., Lowy, M.T., Mason, J.W. (1991). Hypothalamic-pituitary-adrenal dysfunction in posttraumatic stress disorder. *Biol*

[26] Favorite, T.K., Messina, M., Smith, E., Porcari, C. (2009). Group Cognitive Behavioral Analysis System for Psychotherapy in the Treatment of Chronic Comorbid PTSD and Depression. Association for Behavioral and Cognitive Therapies, 41st Annual

[27] Beck A.T., Steer, R.A., Brown, G.K. (1996). Manual for the Beck Depression Inventory-II.

[28] Norris, F.H., Hamblen, J.L. (2004). Standardized self-report measures of civilian trauma and PTSD. In J.P. Wilson, T.M. Keane & T. Martin (Eds.), *Assessing psychological trauma*

[29] Favorite,T.K., Sayegh,L. (2010). Cognitive Behavioral Analysis System of Psychotherapy (CBASP): Adapted to group therapy for outpatients. World Congress of Behavioral and

in non-treatment, community unipolar depressives. Depression, 2, 80-88.

schoolers. *Developmental and Psychopathology*, 3, 397-411.

Sample of Depressed Veterans. Medical Care. 46(8):813-820.

PTSD. *Journal of Affective Disorders,* 2010;121(1-2):165-8.

*Psychiatry*. 15;30(10):1031-48.

Convention, New York, NY

Cognitive Therapies, Boston, MA

San Antonio, TX: Psychological Corporation.

*and PTSD* (pp. 63-102). New York: Guilford Press.

Psychological Science in the Public Interest,11: 1-49.

therapy for PTSD, New York: Guilford Press.

In recent years, the association between depression and cardiovascular disease has been studied extensively (Nicholson *et al.* 2006; Van der Kooy *et al.* 2007). Cardiovascular disease (CVD) refers to those conditions that affect the heart and blood vessels, including amongst others coronary heart disease, cerebrovascular disease, and peripheral artery disease. According to the World Health Organisation, cardiovascular disease now is the primary cause of death around the world. Depressive disorders enhance the development of CVD by both behavioural and biological pathways. They may contribute to unhealthy lifestyle habits that increase cardiovascular risk, such as smoking, low physical activity, and unhealthy diet. Also, this psychiatric condition is associated with activation of the immune system, blood coagulation, hyperactivity of the physiological stress system (e.g. hypothalamic pituitary adrenal axis), and other biological mechanisms which are thought to be involved in de development and progression of CVD. As these behavioural and biological factors are more continuously present in persons with chronic depression, it can be assumed that the risk of developing CVD is even higher in chronically depressed subjects, although this has not been clearly demonstrated yet. The first aim of this Chapter is to summarize what is known about the association between depression and vascular conditions. An overview of the literature will be given and a more detailed description of recent findings from a large Dutch cohort study on depression and anxiety (Seldenrijk *et al.* 2010; Seldenrijk *et al.* 2011b; Vogelzangs *et al.* 2010) will be presented. The second aim is to discuss the relevance of reviewed findings for chronic depression.

## **2. Depression and vascular comorbidity**

## **2.1. Existing evidence on association between depression and CVD**

A recent meta-analysis (Nicholson *et al.* 2006) has reviewed prospective cohort studies that reported on the association between depression and coronary outcomes in healthy

© 2013 Seldenrijk et al., licensee InTech. This is an open access chapter 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. © 2013 Seldenrijk et al., licensee InTech. This is a paper 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.

populations and in coronary heart patients. Twenty-one studies in healthy populations were identified that investigated the incidence of myocardial infarction or fatal coronary heart disease over a mean follow-up period of 10.8 years. It was shown that depression was associated with an 81% increased risk of new coronary events. Studies using clinical measures of depression reported a higher risk than those using symptom scales. Another meta-analysis (Van der Kooy *et al.* 2007), which additionally included cerebrovascular disease outcomes, has shown an even more distinct difference between the effect sizes of clinical depression versus depressive symptoms in association with subsequent CVD (risk ratio of 2.54 versus 1.39, respectively). The authors suggest that this difference may indicate a dose-response relationship between depressed mood and the development of CVD. The meta-analysis by Nicholson and colleagues also identified thirty-four prognostic studies that investigated the association between depression and coronary or all cause mortality in coronary heart patients over a mean follow-up period of 3.2 years (Nicholson *et al.* 2006). Crude results indicated that depressed patients had an 80% higher risk to die during the follow-up compared with non-depressed patients. Results from studies that also adjusted for confounding indicate that 88% of the associations were independent from major coronary risk factors. Although the high risk estimates may be inflated due to incomplete and biased reporting of adjustment, these meta-analytic data provide evidence for depression as a risk factor in the development and course of CVD. In addition, (Carney & Freedland, 2009) have reviewed the literature in order to identify subtypes of depression which are associated with the highest risk of cardiac events in coronary heart patients. They discuss existing evidence from several large clinical trials, such as ENRICHD, MIND-IT, and SADHART. The authors conclude that in particular patients who are unsuccessfully treated for depression following an acute coronary syndrome were found to be at risk for cardiac morbidity or mortality.

Depression, Vascular Conditions and Chronicity 281

to the outside: the intima, the media, and the adventitia (Zarins & Glagov, 2004). The tunica intima is made up of endothelial cells and subendothelial connective tissue. The endothelium, being in direct contact with the blood flow, forms a permeability barrier and thrombo-resistant lining, thereby supporting the artery's conduit function. The tunica media is a thick layer that predominantly consists of elastic fibres and smooth muscle cells. These components are essential for elasticity and contractility, the characteristics needed for cushioning. The adventitia, the outer layer of the arterial wall, is composed of supportive and nutritive tissue, including collagen (a protein that makes up connective tissue) bundles,

Although changes in the structure and function of arterial walls to some extent reflect adaptive processes that are related to age and blood pressure, they also mark 'subclinical' pathophysiological processes which lead to CVD. Two separate, but overlapping conditions that affect medium and large arteries are *athero*sclerosis and *arterio*sclerosis (Mackey *et al.*  2007). Atherosclerosis primarily compromises the conduit functioning of an artery, but is also associated with increased stiffness. Atherosclerosis starts in the intima and includes focal thickening, the formation of athērōmata (literally: tumors full gruel-like matter). Those atheromatous plaques are built up from fatty substances, cholesterol, cellular waste products, calcium and fibrin, and cause the arteries to narrow and be less flexible. Atherosclerosis therefore can (partially) block the oxygen-rich blood supply, leading to ischemic events. Arteriosclerosis, or hardening of the arteries, impairs the cushioning function, and along the line increases the risk of endothelial damage, i.e. atherosclerosis. Arteriosclerosis starts in the media en includes decreasing levels of elastin and increased

One of the ways to measure subclinical atherosclerosis is by calculating the ankle-brachial index (ABI). The ABI is based on potential differences between systolic pressures in arteries of the lower legs and the arms. This measure is used to screen for peripheral arterial disease, but a low ABI (≤0.90; indicative of limited blood flow to the legs) has also been recognized as an indicator of systemic atherosclerosis (Newman *et al.* 1993). Other markers of subclinical atherosclerosis are carotid intima-media thickness (CIMT) and coronary or aortic calcification. CIMT can be measured after visualizing the innermost two layers of the arterial wall by using ultrasonography. Calcification of the coronary arteries or aorta can be identified in 3D images of the heart using electron beam computed tomography. These atherosclerosis markers have shown a predictive value for future incident cardiovascular events (Fowkes *et al.* 2008; Greenland *et al.* 2007; Lorenz *et al.* 2007). Arteriosclerosis also can be detected using various markers of arterial stiffness or endothelial dysfunction (Anderson, 2006). Arterial stiffness can be locally measured using ultrasonography, e.g. by calculating the carotid distensibility coefficient (DC). The DC gives the relative change in cross-sectional area (diameter) per unit of pressure. A measure to estimate aortic stiffness is to analyze

amounts of collagen and calcium, which leads to arterial stiffening.

fibroblasts, and small blood vessels.

*2.2.2. Vascular disease processes*

*2.2.3. Subclinical CVD markers*

This paragraph has illustrated the now large body of literature relating depression to clinical end-points of CVD based on e.g. general practice or hospitalization records. However, the emergence of modern imaging techniques has enabled to study pre- or subclinical cardiovascular outcomes. By examination of subclinical CVD, the temporal sequence and the pathophysiological pathways of the associations might be better understood.

## **2.2. Arteries and subclinical CVD**

Detailed information on different aspects of the cardiovascular burden throughout the body can be obtained using non-invasive methods. Before an overview is given of the research regarding depression and subclinical CVD markers, we will first give some background information on the function and structure of human arteries, and the changes that reflect subclinical disease.

## *2.2.1. Function and structure of arteries*

The arterial tree has a conduit and a cushioning function. The first refers to its delivery of oxygenized blood to bodily organs and tissue, and the second to the converting of an intermittent, pulsatile flow to a more continuous blood flow. With respect to the composition of the arterial wall, three layers or 'tunica' can be distinguished from the inside to the outside: the intima, the media, and the adventitia (Zarins & Glagov, 2004). The tunica intima is made up of endothelial cells and subendothelial connective tissue. The endothelium, being in direct contact with the blood flow, forms a permeability barrier and thrombo-resistant lining, thereby supporting the artery's conduit function. The tunica media is a thick layer that predominantly consists of elastic fibres and smooth muscle cells. These components are essential for elasticity and contractility, the characteristics needed for cushioning. The adventitia, the outer layer of the arterial wall, is composed of supportive and nutritive tissue, including collagen (a protein that makes up connective tissue) bundles, fibroblasts, and small blood vessels.

## *2.2.2. Vascular disease processes*

280 Psychiatric Disorders – New Frontiers in Affective Disorders

populations and in coronary heart patients. Twenty-one studies in healthy populations were identified that investigated the incidence of myocardial infarction or fatal coronary heart disease over a mean follow-up period of 10.8 years. It was shown that depression was associated with an 81% increased risk of new coronary events. Studies using clinical measures of depression reported a higher risk than those using symptom scales. Another meta-analysis (Van der Kooy *et al.* 2007), which additionally included cerebrovascular disease outcomes, has shown an even more distinct difference between the effect sizes of clinical depression versus depressive symptoms in association with subsequent CVD (risk ratio of 2.54 versus 1.39, respectively). The authors suggest that this difference may indicate a dose-response relationship between depressed mood and the development of CVD. The meta-analysis by Nicholson and colleagues also identified thirty-four prognostic studies that investigated the association between depression and coronary or all cause mortality in coronary heart patients over a mean follow-up period of 3.2 years (Nicholson *et al.* 2006). Crude results indicated that depressed patients had an 80% higher risk to die during the follow-up compared with non-depressed patients. Results from studies that also adjusted for confounding indicate that 88% of the associations were independent from major coronary risk factors. Although the high risk estimates may be inflated due to incomplete and biased reporting of adjustment, these meta-analytic data provide evidence for depression as a risk factor in the development and course of CVD. In addition, (Carney & Freedland, 2009) have reviewed the literature in order to identify subtypes of depression which are associated with the highest risk of cardiac events in coronary heart patients. They discuss existing evidence from several large clinical trials, such as ENRICHD, MIND-IT, and SADHART. The authors conclude that in particular patients who are unsuccessfully treated for depression following an

acute coronary syndrome were found to be at risk for cardiac morbidity or mortality.

the pathophysiological pathways of the associations might be better understood.

**2.2. Arteries and subclinical CVD**

*2.2.1. Function and structure of arteries*

subclinical disease.

This paragraph has illustrated the now large body of literature relating depression to clinical end-points of CVD based on e.g. general practice or hospitalization records. However, the emergence of modern imaging techniques has enabled to study pre- or subclinical cardiovascular outcomes. By examination of subclinical CVD, the temporal sequence and

Detailed information on different aspects of the cardiovascular burden throughout the body can be obtained using non-invasive methods. Before an overview is given of the research regarding depression and subclinical CVD markers, we will first give some background information on the function and structure of human arteries, and the changes that reflect

The arterial tree has a conduit and a cushioning function. The first refers to its delivery of oxygenized blood to bodily organs and tissue, and the second to the converting of an intermittent, pulsatile flow to a more continuous blood flow. With respect to the composition of the arterial wall, three layers or 'tunica' can be distinguished from the inside Although changes in the structure and function of arterial walls to some extent reflect adaptive processes that are related to age and blood pressure, they also mark 'subclinical' pathophysiological processes which lead to CVD. Two separate, but overlapping conditions that affect medium and large arteries are *athero*sclerosis and *arterio*sclerosis (Mackey *et al.*  2007). Atherosclerosis primarily compromises the conduit functioning of an artery, but is also associated with increased stiffness. Atherosclerosis starts in the intima and includes focal thickening, the formation of athērōmata (literally: tumors full gruel-like matter). Those atheromatous plaques are built up from fatty substances, cholesterol, cellular waste products, calcium and fibrin, and cause the arteries to narrow and be less flexible. Atherosclerosis therefore can (partially) block the oxygen-rich blood supply, leading to ischemic events. Arteriosclerosis, or hardening of the arteries, impairs the cushioning function, and along the line increases the risk of endothelial damage, i.e. atherosclerosis. Arteriosclerosis starts in the media en includes decreasing levels of elastin and increased amounts of collagen and calcium, which leads to arterial stiffening.

#### *2.2.3. Subclinical CVD markers*

One of the ways to measure subclinical atherosclerosis is by calculating the ankle-brachial index (ABI). The ABI is based on potential differences between systolic pressures in arteries of the lower legs and the arms. This measure is used to screen for peripheral arterial disease, but a low ABI (≤0.90; indicative of limited blood flow to the legs) has also been recognized as an indicator of systemic atherosclerosis (Newman *et al.* 1993). Other markers of subclinical atherosclerosis are carotid intima-media thickness (CIMT) and coronary or aortic calcification. CIMT can be measured after visualizing the innermost two layers of the arterial wall by using ultrasonography. Calcification of the coronary arteries or aorta can be identified in 3D images of the heart using electron beam computed tomography. These atherosclerosis markers have shown a predictive value for future incident cardiovascular events (Fowkes *et al.* 2008; Greenland *et al.* 2007; Lorenz *et al.* 2007). Arteriosclerosis also can be detected using various markers of arterial stiffness or endothelial dysfunction (Anderson, 2006). Arterial stiffness can be locally measured using ultrasonography, e.g. by calculating the carotid distensibility coefficient (DC). The DC gives the relative change in cross-sectional area (diameter) per unit of pressure. A measure to estimate aortic stiffness is to analyze pulse waves or contours, derived by applanation tonometry. The arterial pressure waveform consists of a forward wave which is created by ejection and a backward wave caused by reflection (e.g. at bifurcations). The central augmentation index (AIx) estimates the percentage of augmented late systolic pressure due to arterial stiffness. Indicators of arterial stiffness have shown capable of predicting future cardiovascular events (Adji *et al.* 2011; Laurent *et al.* 2006).

Depression, Vascular Conditions and Chronicity 283

These observations are indicative of an association between depression and subclinical CVD. However, for both atherosclerosis and arteriosclerosis, there are still doubts on the generalizability of the observations since sample sizes of existing studies often were small, and many studies were performed in older or diseased populations. In a large Dutch cohort study some of these limitations could be overcome. This study addresses both depression and anxiety, since these are highly concurrent disorders (Kessler *et al.* 2005) with partially

NESDA is an ongoing longitudinal cohort study to examine the prevalence, course and consequences of depressive and anxiety disorders. In order to represent various health care settings and stages of psychopathology, participants were recruited from community (19%), primary care (54%) and outpatient psychiatric clinics (27%). Participants were men and women, aged 18-65 years at the baseline assessment in 2004-2007. Individuals with remitted and current depressive or anxiety disorders, as well as healthy controls were included. Details of the study rationale, recruitment strategy and methods are described elsewhere (Penninx *et al.* 2008). Based on NESDA baseline and 2-year follow up data, associations between depression, anxiety and several vascular conditions have been investigated in large samples (see flow chart, figure 1). The methods and results of three publications (Seldenrijk

*et al.* 2010; Seldenrijk *et al.* 2011b; Vogelzangs *et al.* 2010) are being described below.

The assessment included amongst others a blood draw, a medical examination, administration of several written questionnaires concerning, e.g., mood state, lifestyle, and medical history, a psychiatric interview, and an interview regarding somatic health aspects. Diagnoses of depressive disorders (major depression, dysthymia) and anxiety disorders (generalized anxiety disorder, panic disorder, agoraphobia, social phobia) were established using the DSM-IV based Composite International Diagnostic Interview. In addition, clinical characteristics of these disorders were assessed. Severity of symptoms was measured with the 30-item Inventory of Depressive Symptomatology self-report version and the 21-item Beck Anxiety Inventory. Duration of symptoms was assessed using the Life Chart method (Lyketsos *et al.* 1994), after which the percentage of time with symptoms during the past few years was computed. Psychoactive medication use was assessed based on drug container inspection of all drugs used in the past month and classified according to the WHO Anatomical Therapeutic Chemical classification. Psychoactive medication included selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), other antidepressants

The presence of CVD at the baseline assessment was adjudicated using standardized algorithms considering self-report and medication use based on drug container inspection.

overlapping symptoms (Hiller *et al.* 1989).

*2.4.1. Sample*

*2.4.2. Methods*

and benzodiazepines.

**2.4. Netherlands Study of Depression and Anxiety (NESDA)**

## **2.3. Existing evidence on association between depression and subclinical CVD**

Studies investigating the association between depression and the ABI have yielded conflicting results. One prospective study used low ABI amongst other measures to define incident peripheral arterial disease in a middle-aged population and found moderate or high levels of depressive symptoms to be associated with an 20% and 44% increased risk (Wattanakit *et al.* 2005). In contrast, two studies found no association between depressed mood and low ABI among older men and women. This lack of a significant association might have been due to a low prevalence of depressive disorder (3%) in the populationbased Rotterdam Study (Tiemeier *et al.* 2004) or to a relatively small sample size (n=167) in the other study which was carried out in patients with peripheral arterial disease and controls (Arseven *et al.* 2001). Literature on the association between depression and other markers of subclinical atherosclerosis shows a similar inconclusiveness as the ABI research. Some studies – based on middle-aged or older individuals – have shown a positive association between depression and CIMT(Chen *et al.* 2006; Elovainio *et al.* 2005; Paterniti *et al.* 2001; Stewart *et al.* 2007; Tiemeier *et al.* 2004; Whipple *et al.* 2009), whereas other studies have found no association (Jones *et al.* 2003; Matthews *et al.* 1998; Narita *et al.* 2008; Rice *et al.*  2009; Seldenrijk *et al.* 2011a; Spitzer *et al.* 2008). Likewise, depression has been associated with coronary or aortic calcification in some (Agatisa *et al.* 2005; Hamer *et al.* 2010; Matthews *et al.* 2010; Tiemeier *et al.* 2004), but not in other (Diez Roux *et al.* 2006; O'Malley *et al.* 2000) studies. An interesting observation with respect to chronicity of depression is that the positive findings for depression and calcification were particularly found for long-term poor mental health as indicated by recurrent depressive episodes or repeatedly measured depressive symptoms.

Studies investigating the association between depression and arteriosclerosis have used a variety of indexes for vascular function (Lavoie *et al.* 2010; Oulis *et al.* 2010; Paranthaman *et al.* 2010; Rajagopalan *et al.* 2001; Rybakowski *et al.* 2006; Sherwood *et al.* 2005; Tiemeier *et al.*  2003). Irrespective of these different outcome measures, all studies unanimously have shown depressed individuals to have impaired endothelial function or increased arterial stiffness. The association may be influenced by psychiatric characteristics, such as chronicity of symptoms, but evidence for this idea is still meager. In older diabetic women, recurrent but not single episode depression was associated with endothelial dysfunction (Wagner *et al.* 2009). In initially severely depressed women, successful antidepressant treatment was followed by a restoration of vascular function (Oulis *et al.* 2010). Additionally, preliminary evidence from a case-control study (Paranthaman *et al.* 2012) suggests that non-response to antidepressant monotherapy in late-life is related to increased endothelial dysfunction (n=31) and CIMT (n=45).

These observations are indicative of an association between depression and subclinical CVD. However, for both atherosclerosis and arteriosclerosis, there are still doubts on the generalizability of the observations since sample sizes of existing studies often were small, and many studies were performed in older or diseased populations. In a large Dutch cohort study some of these limitations could be overcome. This study addresses both depression and anxiety, since these are highly concurrent disorders (Kessler *et al.* 2005) with partially overlapping symptoms (Hiller *et al.* 1989).

## **2.4. Netherlands Study of Depression and Anxiety (NESDA)**

## *2.4.1. Sample*

282 Psychiatric Disorders – New Frontiers in Affective Disorders

Laurent *et al.* 2006).

depressive symptoms.

(n=31) and CIMT (n=45).

pulse waves or contours, derived by applanation tonometry. The arterial pressure waveform consists of a forward wave which is created by ejection and a backward wave caused by reflection (e.g. at bifurcations). The central augmentation index (AIx) estimates the percentage of augmented late systolic pressure due to arterial stiffness. Indicators of arterial stiffness have shown capable of predicting future cardiovascular events (Adji *et al.* 2011;

**2.3. Existing evidence on association between depression and subclinical CVD**

Studies investigating the association between depression and the ABI have yielded conflicting results. One prospective study used low ABI amongst other measures to define incident peripheral arterial disease in a middle-aged population and found moderate or high levels of depressive symptoms to be associated with an 20% and 44% increased risk (Wattanakit *et al.* 2005). In contrast, two studies found no association between depressed mood and low ABI among older men and women. This lack of a significant association might have been due to a low prevalence of depressive disorder (3%) in the populationbased Rotterdam Study (Tiemeier *et al.* 2004) or to a relatively small sample size (n=167) in the other study which was carried out in patients with peripheral arterial disease and controls (Arseven *et al.* 2001). Literature on the association between depression and other markers of subclinical atherosclerosis shows a similar inconclusiveness as the ABI research. Some studies – based on middle-aged or older individuals – have shown a positive association between depression and CIMT(Chen *et al.* 2006; Elovainio *et al.* 2005; Paterniti *et al.* 2001; Stewart *et al.* 2007; Tiemeier *et al.* 2004; Whipple *et al.* 2009), whereas other studies have found no association (Jones *et al.* 2003; Matthews *et al.* 1998; Narita *et al.* 2008; Rice *et al.*  2009; Seldenrijk *et al.* 2011a; Spitzer *et al.* 2008). Likewise, depression has been associated with coronary or aortic calcification in some (Agatisa *et al.* 2005; Hamer *et al.* 2010; Matthews *et al.* 2010; Tiemeier *et al.* 2004), but not in other (Diez Roux *et al.* 2006; O'Malley *et al.* 2000) studies. An interesting observation with respect to chronicity of depression is that the positive findings for depression and calcification were particularly found for long-term poor mental health as indicated by recurrent depressive episodes or repeatedly measured

Studies investigating the association between depression and arteriosclerosis have used a variety of indexes for vascular function (Lavoie *et al.* 2010; Oulis *et al.* 2010; Paranthaman *et al.* 2010; Rajagopalan *et al.* 2001; Rybakowski *et al.* 2006; Sherwood *et al.* 2005; Tiemeier *et al.*  2003). Irrespective of these different outcome measures, all studies unanimously have shown depressed individuals to have impaired endothelial function or increased arterial stiffness. The association may be influenced by psychiatric characteristics, such as chronicity of symptoms, but evidence for this idea is still meager. In older diabetic women, recurrent but not single episode depression was associated with endothelial dysfunction (Wagner *et al.* 2009). In initially severely depressed women, successful antidepressant treatment was followed by a restoration of vascular function (Oulis *et al.* 2010). Additionally, preliminary evidence from a case-control study (Paranthaman *et al.* 2012) suggests that non-response to antidepressant monotherapy in late-life is related to increased endothelial dysfunction NESDA is an ongoing longitudinal cohort study to examine the prevalence, course and consequences of depressive and anxiety disorders. In order to represent various health care settings and stages of psychopathology, participants were recruited from community (19%), primary care (54%) and outpatient psychiatric clinics (27%). Participants were men and women, aged 18-65 years at the baseline assessment in 2004-2007. Individuals with remitted and current depressive or anxiety disorders, as well as healthy controls were included. Details of the study rationale, recruitment strategy and methods are described elsewhere (Penninx *et al.* 2008). Based on NESDA baseline and 2-year follow up data, associations between depression, anxiety and several vascular conditions have been investigated in large samples (see flow chart, figure 1). The methods and results of three publications (Seldenrijk *et al.* 2010; Seldenrijk *et al.* 2011b; Vogelzangs *et al.* 2010) are being described below.

#### *2.4.2. Methods*

The assessment included amongst others a blood draw, a medical examination, administration of several written questionnaires concerning, e.g., mood state, lifestyle, and medical history, a psychiatric interview, and an interview regarding somatic health aspects. Diagnoses of depressive disorders (major depression, dysthymia) and anxiety disorders (generalized anxiety disorder, panic disorder, agoraphobia, social phobia) were established using the DSM-IV based Composite International Diagnostic Interview. In addition, clinical characteristics of these disorders were assessed. Severity of symptoms was measured with the 30-item Inventory of Depressive Symptomatology self-report version and the 21-item Beck Anxiety Inventory. Duration of symptoms was assessed using the Life Chart method (Lyketsos *et al.* 1994), after which the percentage of time with symptoms during the past few years was computed. Psychoactive medication use was assessed based on drug container inspection of all drugs used in the past month and classified according to the WHO Anatomical Therapeutic Chemical classification. Psychoactive medication included selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), other antidepressants and benzodiazepines.

The presence of CVD at the baseline assessment was adjudicated using standardized algorithms considering self-report and medication use based on drug container inspection. CVD included stroke and coronary heart disease, i.e. angina pectoris, myocardial infarction, percutaneous transluminal coronary angioplasty and coronary artery bypass grafting. Cardiovascular surgery was based on self-report alone, whereas other reported CVD conditions were only considered present when self-report was supported by the use of medication. Subclinical atherosclerosis was indicated by the ABI, measured using a Doppler ultrasound at the baseline assessment. In line with recommendations from the Ankle Brachial Index Collaboration, three groups of increased cardiovascular risk were distinguished: low ABI (0.90 or less) and mildly low ABI (ranging 0.90 to 1.11), but also high ABI (greater than 1.40) (Fowkes *et al.* 2008). ABI analyses were conducted in subjects without known CVD. Two year after baseline, 87.1% of the NESDA sample took part in a follow-up visit. A subsample of these participants was then recruited for additional cardiovascular measurements, including two different indicators of arterial stiffness (Seldenrijk *et al.* 2011b). The carotid DC was measured using M-mode ultrasound scanning. In addition, the central AIx was estimated by using radial pulse wave analysis.

Depression, Vascular Conditions and Chronicity 285

significant association was found between depression or anxiety and stroke, nor between remitted diagnoses and CVD. Of the psychiatric characteristics, severity of depressive or anxiety symptoms was positively associated with coronary heart disease in a dose-response manner. No significant associations were found for duration of psychiatric symptoms prior

The prevalence of a low ABI was 2.2% in the CVD-free baseline population. People with a current diagnosis of depression or anxiety disorder almost 3-times more often had a low ABI as compared with controls. This increased likelihood in currently depressed or anxious was independent of sociodemographic factors, hypertension, diabetes and lifestyle factors. No increased risk was found for those with remitted diagnoses of depression or anxiety disorders. Possible explanations for this are decreased reliability of remitted diagnoses because of their retrospective character and that they indicate less severe exposure to psychological distress, the current group more frequently including chronic and relapsing cases. Psychiatric characteristics, such as severity and duration of depressive or anxiety symptoms prior to baseline, or the use of antidepressant medication, did not further differentiate the risk of low ABI in depressed and anxious subjects. No association was found between depression or

anxiety and mildly low (prevalence 35.7%) or high (prevalence 2.5%) ABI.

reuptake inhibitors (SNRIs) showed significantly increased AIx.

**Figure 2.** Association between symptom severity or duration and central arterial stiffness (AIx in %)

People with a current depressive or anxiety disorder at the NESDA 2-year assessment showed an increased central arterial stiffness as compared with controls. Again, those who had suffered from a depressed or anxious episode in the past but were currently recovered, did not differ from controls with respect to arterial stiffness. In addition to earlier mentioned explanations (i.e. reliability, chronicity), this could also imply that arterial status returns to normal when people recover from depression or anxiety. Evidence for a dose-response relationship was provided in our observations of an increased AIx in subjects who were longer or more severely exposed to depressive or anxiety symptoms over time (see fig. 2). No significant associations were found for carotid DC, although the duration of depressive and anxiety symptoms tended to be associated with a higher carotid artery stiffness. To rule out the possibility that observed associations were driven by subjects with known CVD or diabetes, or using antihypertensive or lipid-modifying medication, analyses were repeated without those cases and results remained similar. After exclusion of participants with suspected cardiovascular health, those using TCAs or combined serotonin/noradrenaline

to baseline or use of psychotropic medication.

**Figure 1.** Flow chart of study population per vascular outcome

## *2.4.3. Results*

The prevalence of CVD in the NESDA baseline population was 5.6%. First, depressive and anxiety disorders were analyzed separately. After adjustment for sociodemographics and lifestyle factors, people with a current depression (odds ratio of 1.6) and those with a current anxiety disorder (odds ratio of 2.2) showed increased likelihood of having CVD as compared with those who never had a depressive or anxious episode. When combining the presence or absence of both psychiatric conditions in one categorical variable, only people with a current anxiety disorder with or without co-morbid depression more often had coronary heart disease. The adjusted odds were 2.7 for subjects who only had a diagnosis of anxiety disorder and 3.5 for those who also had a co-morbid depressive disorder. No significant association was found between depression or anxiety and stroke, nor between remitted diagnoses and CVD. Of the psychiatric characteristics, severity of depressive or anxiety symptoms was positively associated with coronary heart disease in a dose-response manner. No significant associations were found for duration of psychiatric symptoms prior to baseline or use of psychotropic medication.

284 Psychiatric Disorders – New Frontiers in Affective Disorders

AIx was estimated by using radial pulse wave analysis.

NESDA baseline population n=2981

NESDA 2-year population n=2596

**Figure 1.** Flow chart of study population per vascular outcome

The prevalence of CVD in the NESDA baseline population was 5.6%. First, depressive and anxiety disorders were analyzed separately. After adjustment for sociodemographics and lifestyle factors, people with a current depression (odds ratio of 1.6) and those with a current anxiety disorder (odds ratio of 2.2) showed increased likelihood of having CVD as compared with those who never had a depressive or anxious episode. When combining the presence or absence of both psychiatric conditions in one categorical variable, only people with a current anxiety disorder with or without co-morbid depression more often had coronary heart disease. The adjusted odds were 2.7 for subjects who only had a diagnosis of anxiety disorder and 3.5 for those who also had a co-morbid depressive disorder. No

Arterial stiffness measurements n=618

Cardiovascular disease assessment n=2807

> Atherosclerosis measurements n=2717

*2.4.3. Results*

CVD included stroke and coronary heart disease, i.e. angina pectoris, myocardial infarction, percutaneous transluminal coronary angioplasty and coronary artery bypass grafting. Cardiovascular surgery was based on self-report alone, whereas other reported CVD conditions were only considered present when self-report was supported by the use of medication. Subclinical atherosclerosis was indicated by the ABI, measured using a Doppler ultrasound at the baseline assessment. In line with recommendations from the Ankle Brachial Index Collaboration, three groups of increased cardiovascular risk were distinguished: low ABI (0.90 or less) and mildly low ABI (ranging 0.90 to 1.11), but also high ABI (greater than 1.40) (Fowkes *et al.* 2008). ABI analyses were conducted in subjects without known CVD. Two year after baseline, 87.1% of the NESDA sample took part in a follow-up visit. A subsample of these participants was then recruited for additional cardiovascular measurements, including two different indicators of arterial stiffness (Seldenrijk *et al.* 2011b). The carotid DC was measured using M-mode ultrasound scanning. In addition, the central

The prevalence of a low ABI was 2.2% in the CVD-free baseline population. People with a current diagnosis of depression or anxiety disorder almost 3-times more often had a low ABI as compared with controls. This increased likelihood in currently depressed or anxious was independent of sociodemographic factors, hypertension, diabetes and lifestyle factors. No increased risk was found for those with remitted diagnoses of depression or anxiety disorders. Possible explanations for this are decreased reliability of remitted diagnoses because of their retrospective character and that they indicate less severe exposure to psychological distress, the current group more frequently including chronic and relapsing cases. Psychiatric characteristics, such as severity and duration of depressive or anxiety symptoms prior to baseline, or the use of antidepressant medication, did not further differentiate the risk of low ABI in depressed and anxious subjects. No association was found between depression or anxiety and mildly low (prevalence 35.7%) or high (prevalence 2.5%) ABI.

**Figure 2.** Association between symptom severity or duration and central arterial stiffness (AIx in %)

People with a current depressive or anxiety disorder at the NESDA 2-year assessment showed an increased central arterial stiffness as compared with controls. Again, those who had suffered from a depressed or anxious episode in the past but were currently recovered, did not differ from controls with respect to arterial stiffness. In addition to earlier mentioned explanations (i.e. reliability, chronicity), this could also imply that arterial status returns to normal when people recover from depression or anxiety. Evidence for a dose-response relationship was provided in our observations of an increased AIx in subjects who were longer or more severely exposed to depressive or anxiety symptoms over time (see fig. 2). No significant associations were found for carotid DC, although the duration of depressive and anxiety symptoms tended to be associated with a higher carotid artery stiffness. To rule out the possibility that observed associations were driven by subjects with known CVD or diabetes, or using antihypertensive or lipid-modifying medication, analyses were repeated without those cases and results remained similar. After exclusion of participants with suspected cardiovascular health, those using TCAs or combined serotonin/noradrenaline reuptake inhibitors (SNRIs) showed significantly increased AIx.

## **3. Summary and relevance for chronic depression**

At this point in time there is a paucity of research that directly compares chronic versus nonchronic depression in association with the development of CVD. This paragraph summarizes the evidence regarding an association between depression and vascular conditions as presented above. In addition, inferences are made on the relevance of the reviewed evidence for a chronically depressed population.

Depression, Vascular Conditions and Chronicity 287

psychiatric condition, such as depressive disorder, can be considered a high risk population. One explanation for the divergence between current and remitted diagnoses is that the group with current psychopathology also includes people who are chronically affected by, or frequently relapse into, depressive or anxious episodes. As compared with a remitted diagnosis, a current diagnosis thus might indicate a more sustained exposure to psychological distress. Our study on arterial stiffness (Seldenrijk *et al.* 2011b) did provide more direct support for a cumulative effect: the higher the percentage of time affected by depressed or anxious symptoms, the stiffer one's arteries were. Although depression was not significantly associated with CVD independent of anxiety in (Vogelzangs *et al.* 2010), it was demonstrated that participants with both current anxiety and depression carried the highest risk of having coronary heart disease. The additive effect of different psychiatric conditions (e.g. panic disorder and depression) on vascular health previously had been described by (Gomez-Caminero *et al.* 2005). These individuals who suffer from both depression and anxiety at the same time might well define a chronically depressed population. This hypothesis is supported by prospective data from the NESDA cohort, which indicated that a chronic course of depressive disorder is predicated by having a comorbid anxiety disorder (Penninx *et al.* 2011)*.* In line with this, other studies (e.g. (Fava *et al.*  2008)) have found that depressed patients with high levels of anxiety are less likely to

As mentioned before, the observations discussed are not without inconsistencies. Some studies did not find significant associations between depression and subclinical atherosclerosis. Likewise, our own studies provided no evidence for an association between depression and stroke or carotid arterial stiffness, nor did we find an effect of the duration of depressive symptoms on some vascular outcomes. These discrepancies across studies could be due to differences in populations and in vascular outcome measures. At a younger age, the prevalence of clinical CVD is not very high, and the range of aberrant subclinical values is not wide. As a consequence, associations are hard to be detected. Linked to this point, a differential impact (i.e. rate and severity) of aging across the arterial tree might also partially explain the discrepant findings. It has been demonstrated that subclinical atherosclerosis probably does not affect all arterial beds in a uniform and contemporaneous manner (DeCara, 2011). This may be due to differential composition of the vascular wall

(elastic versus muscular arteries) as well as the location of the arteries in the body.

The association between chronic depression and CVD has also received support from other lines of research. First, it has been suggested that specific subtypes of depression may be partly caused by CVD or cardiovascular risk factors. Some evidence exists that these subtypes are more chronic in course. One of the primary criteria of a 'vascular depression' (Alexopoulos *et al.* 1997) is clinical or subclinical evidence of cerebrovascular impairment. Another potential characteristic of this depression subtype is a late first onset of someone's first depressive episode. Patients with vascular depression seem to be less likely to respond to antidepressant treatment (Navarro *et al.* 2004; Patankar *et al.* 2007). Likewise, the metabolic syndrome has been investigated as a prognostic factor for the course of depressive disorder. Metabolic syndrome is a combination of cardiovascular risk factors (Mottillo *et al.*

respond to treatment.

Meta-analytic data have shown that depression increases one's risk to develop CVD (Nicholson *et al.* 2006; Van der Kooy *et al.* 2007) and to have an unfavourable course of CVD with more cardiac events and higher mortality rates (Nicholson *et al.* 2006) (see paragraph 2.1). Included studies that investigated clinical depression showed larger effect sizes than those using symptom lists. This may suggest that a more sustained exposure to psychological distress results in a dose-response effect on cardiovascular outcomes. Although the studies in these meta-analyses had no primary focus on chronic depression, it can thus be argued that chronically depressed patients have a particularly increased cardiovascular risk. A literature review of studies in coronary heart patients has supported this idea for depression as a prognostic factor: patients with treatment resistant depression more than responders were at risk for an unfavourable course of CVD (Carney & Freedland, 2009).

The mostly cross-sectional studies that investigated depression in relation to subclinical atherosclerosis are still inconclusive (see paragraph 2.3). Some studies failed to provide evidence for a higher cardiovascular risk in depression. However, other studies did find significant associations for either subclinical atherosclerosis or arteriosclerosis. Certain observations are of special interest, since they seem to point out that people suffering from long-lasting or treatment resistant depression constitute a distinctly high-risk group. Studies that demonstrated depression to be associated with a higher prevalence of aortic or coronary calcification found this either in participants who repeatedly reported high depressive symptoms (Hamer *et al.* 2010), or in those with recurrent depressive episodes (Agatisa *et al.*  2005; Matthews *et al.* 2010). Also with respect to CIMT and endothelial function, a gradient has been shown across groups, with non-depressed control subjects having the best vascular structure or function, antidepressant non-responders worse and responders in-between (Paranthaman *et al.* 2012).

Based on our studies (Seldenrijk *et al.* 2010; Seldenrijk *et al.* 2011b; Vogelzangs *et al.* 2010), it can be concluded that people with a current depressive or anxiety disorder have a higher likelihood of coronary heart disease and peripheral atherosclerosis and increased central arterial stiffness (see paragraph 2.4.3). No significant associations were found for remitted disorders. Psychiatric characteristics that in some way differentiated the CVD risk were severity of symptoms (coronary disease, central arterial stiffness) and duration of symptoms (arterial stiffness). In all three studies, a current diagnosis of depression or anxiety was associated with an increased likelihood of vascular conditions. No significant associations were found for subjects with remitted disorders. Since emotional distress likely exerts its effects on the arteries in a cumulative manner, people who chronically suffer from a psychiatric condition, such as depressive disorder, can be considered a high risk population. One explanation for the divergence between current and remitted diagnoses is that the group with current psychopathology also includes people who are chronically affected by, or frequently relapse into, depressive or anxious episodes. As compared with a remitted diagnosis, a current diagnosis thus might indicate a more sustained exposure to psychological distress. Our study on arterial stiffness (Seldenrijk *et al.* 2011b) did provide more direct support for a cumulative effect: the higher the percentage of time affected by depressed or anxious symptoms, the stiffer one's arteries were. Although depression was not significantly associated with CVD independent of anxiety in (Vogelzangs *et al.* 2010), it was demonstrated that participants with both current anxiety and depression carried the highest risk of having coronary heart disease. The additive effect of different psychiatric conditions (e.g. panic disorder and depression) on vascular health previously had been described by (Gomez-Caminero *et al.* 2005). These individuals who suffer from both depression and anxiety at the same time might well define a chronically depressed population. This hypothesis is supported by prospective data from the NESDA cohort, which indicated that a chronic course of depressive disorder is predicated by having a comorbid anxiety disorder (Penninx *et al.* 2011)*.* In line with this, other studies (e.g. (Fava *et al.*  2008)) have found that depressed patients with high levels of anxiety are less likely to respond to treatment.

286 Psychiatric Disorders – New Frontiers in Affective Disorders

2009).

(Paranthaman *et al.* 2012).

**3. Summary and relevance for chronic depression**

reviewed evidence for a chronically depressed population.

At this point in time there is a paucity of research that directly compares chronic versus nonchronic depression in association with the development of CVD. This paragraph summarizes the evidence regarding an association between depression and vascular conditions as presented above. In addition, inferences are made on the relevance of the

Meta-analytic data have shown that depression increases one's risk to develop CVD (Nicholson *et al.* 2006; Van der Kooy *et al.* 2007) and to have an unfavourable course of CVD with more cardiac events and higher mortality rates (Nicholson *et al.* 2006) (see paragraph 2.1). Included studies that investigated clinical depression showed larger effect sizes than those using symptom lists. This may suggest that a more sustained exposure to psychological distress results in a dose-response effect on cardiovascular outcomes. Although the studies in these meta-analyses had no primary focus on chronic depression, it can thus be argued that chronically depressed patients have a particularly increased cardiovascular risk. A literature review of studies in coronary heart patients has supported this idea for depression as a prognostic factor: patients with treatment resistant depression more than responders were at risk for an unfavourable course of CVD (Carney & Freedland,

The mostly cross-sectional studies that investigated depression in relation to subclinical atherosclerosis are still inconclusive (see paragraph 2.3). Some studies failed to provide evidence for a higher cardiovascular risk in depression. However, other studies did find significant associations for either subclinical atherosclerosis or arteriosclerosis. Certain observations are of special interest, since they seem to point out that people suffering from long-lasting or treatment resistant depression constitute a distinctly high-risk group. Studies that demonstrated depression to be associated with a higher prevalence of aortic or coronary calcification found this either in participants who repeatedly reported high depressive symptoms (Hamer *et al.* 2010), or in those with recurrent depressive episodes (Agatisa *et al.*  2005; Matthews *et al.* 2010). Also with respect to CIMT and endothelial function, a gradient has been shown across groups, with non-depressed control subjects having the best vascular structure or function, antidepressant non-responders worse and responders in-between

Based on our studies (Seldenrijk *et al.* 2010; Seldenrijk *et al.* 2011b; Vogelzangs *et al.* 2010), it can be concluded that people with a current depressive or anxiety disorder have a higher likelihood of coronary heart disease and peripheral atherosclerosis and increased central arterial stiffness (see paragraph 2.4.3). No significant associations were found for remitted disorders. Psychiatric characteristics that in some way differentiated the CVD risk were severity of symptoms (coronary disease, central arterial stiffness) and duration of symptoms (arterial stiffness). In all three studies, a current diagnosis of depression or anxiety was associated with an increased likelihood of vascular conditions. No significant associations were found for subjects with remitted disorders. Since emotional distress likely exerts its effects on the arteries in a cumulative manner, people who chronically suffer from a As mentioned before, the observations discussed are not without inconsistencies. Some studies did not find significant associations between depression and subclinical atherosclerosis. Likewise, our own studies provided no evidence for an association between depression and stroke or carotid arterial stiffness, nor did we find an effect of the duration of depressive symptoms on some vascular outcomes. These discrepancies across studies could be due to differences in populations and in vascular outcome measures. At a younger age, the prevalence of clinical CVD is not very high, and the range of aberrant subclinical values is not wide. As a consequence, associations are hard to be detected. Linked to this point, a differential impact (i.e. rate and severity) of aging across the arterial tree might also partially explain the discrepant findings. It has been demonstrated that subclinical atherosclerosis probably does not affect all arterial beds in a uniform and contemporaneous manner (DeCara, 2011). This may be due to differential composition of the vascular wall (elastic versus muscular arteries) as well as the location of the arteries in the body.

The association between chronic depression and CVD has also received support from other lines of research. First, it has been suggested that specific subtypes of depression may be partly caused by CVD or cardiovascular risk factors. Some evidence exists that these subtypes are more chronic in course. One of the primary criteria of a 'vascular depression' (Alexopoulos *et al.* 1997) is clinical or subclinical evidence of cerebrovascular impairment. Another potential characteristic of this depression subtype is a late first onset of someone's first depressive episode. Patients with vascular depression seem to be less likely to respond to antidepressant treatment (Navarro *et al.* 2004; Patankar *et al.* 2007). Likewise, the metabolic syndrome has been investigated as a prognostic factor for the course of depressive disorder. Metabolic syndrome is a combination of cardiovascular risk factors (Mottillo *et al.*  2010), including abdominal obesity, lipid abnormalities, hypertension, and hyperglycaemia. Based on a community sample of older persons, (Vogelzangs *et al.* 2011) found that depressed subjects with metabolic syndrome ('metabolic depression') were almost 3-fold more likely to have persistent or recurrent depression. In addition, depression and more specifically treatment resistant depression has been associated with inflammation (Miller *et al.* 2009). Since inflammation is considered one of the important mechanisms that enhance the development of CVD (Willerson & Ridker, 2004), individuals who are nonresponsive to antidepressant treatment may have a higher likelihood of future cardiovascular events. Furthermore, specific types of antidepressant medications (e.g. TCAs and SNRIs) have been associated with unfavourable side-effects on metabolism, sympathetic activity and the immune system (Licht *et al.* 2012; van Reedt Dortland *et al.* 2010; Vogelzangs *et al.* 2012). Although the prospective nature of some evidence suggests that active ingredients of the antidepressants might be responsible (Licht *et al.* 2012), it also is likely that patients who use these antidepressants differ from non-users or SSRI users by having more severe and more chronic psychopathology.

Depression, Vascular Conditions and Chronicity 289

a chronic depression or with both depressive and anxiety disorders) regular measurements of blood pressure, cholesterol and glucose levels could be incorporated as a matter of standard practice. In addition, because of the increased prevalence of (subclinical) CVD in this population, extra attention to a healthy lifestyle appears an important aspect of the treatment of depressed patients. As to the primary target of cardiovascular risk intervention,

"Adoption of healthy life habits remains the cornerstone of primary prevention, including the avoidance of tobacco (including second-hand smoke), healthy dietary patterns, weight control, and regular, appropriate exercise. An important role of healthcare providers is to support and reinforce these public health recommendations

Regarding exercise, some inspiring observations for the improvement of both mental and vascular health have recently been published: physical activity reduces the risk of CVD events (Hamer *et al.* 2011) and positively influences depressive complaints (Carek *et al.* 2011; Hoffman *et al.* 2011). The reinforcing and supporting role thus also fits professionals in the field of chronic depression, particularly since a tendency to ignore cardiovascular symptoms

Adji, A., O'Rourke, M.F. & Namasivayam, M. (2011). Arterial stiffness, its assessment,

Agatisa, P.K., Matthews, K.A., Bromberger, J.T., Edmundowicz, D., Chang, Y.F. & Sutton-Tyrrell, K. (2005). Coronary and aortic calcification in women with a history of major

Alexopoulos, G.S., Meyers, B.S., Young, R.C., Campbell, S., Silbersweig, D. & Charlson, M.

Anderson, T.J. (2006). Arterial stiffness or endothelial dysfunction as a surrogate marker of

Arseven, A., Guralnik, J.M., O'Brien, E., Liu, K. & McDermott, M.M. (2001). Peripheral arterial disease and depressed mood in older men and women. *Vasc.Med* 6(4):229-234. Berkman, L.F., Blumenthal, J., Burg, M., Carney, R.M., Catellier, D., Cowan, M.J., Czajkowski, S.M., DeBusk, R., Hosking, J., Jaffe, A., Kaufmann, P.G., Mitchell, P., Norman, J., Powell, L.H., Raczynski, J.M. & Schneiderman, N. (2003). Effects of treating depression and low perceived social support on clinical events after myocardial

prognostic value, and implications for treatment. *Am J Hypertens.* 24(1):5-17.

(1997). 'Vascular depression' hypothesis. *Arch.Gen.Psychiatry* 54(10):915-922.

and taking action from it might be inherent in serious mental illnesses.

Adrie Seldenrijk, Nicole Vogelzangs, Patricia van Oppen,

depression. *Arch.Intern.Med* 165(11):1229-1236.

vascular risk. *Can.J Cardiol.* 22 Suppl B:72B-80B.

*Department of Psychiatry, Vrije Universiteit, Amsterdam, Netherlands*

Brenda Penninx and Anneke van Schaik

the American Heart Associations has stated:

for all patients." (Pearson *et al.* 2002)

**Author details**

**5. References**

## **4. Possible implications**

The above reviewed epidemiological evidence seems to indicate that chronic depression can be considered a cardiovascular risk factor. The question now arises of how this knowledge may be useful in clinical practice. First, modification of the risk factor would be expected to have beneficial effects on vascular health. Apart from the challenge this by definition means in chronic depression, it is still unknown whether successful treatment of depression indeed leads to improvement in cardiovascular morbidity and mortality. As for now, randomized controlled trials in CVD-free populations have not yet been carried out. Some trials (SADHART, (Glassman *et al.* 2002); ENRICHD, (Berkman *et al.* 2003); MIND-IT, (van Melle *et al.* 2007)) did investigate the effects of antidepressant psychotherapy or pharmacotherapy on cardiovascular morbidity and mortality in coronary patient populations. Although these studies have shown that depression is treatable in coronary patients, no significant differences were found in medical end-points between intervention and control groups. However, (Carney & Freedland, 2007) have pointed out that future studies are still needed to reinvestigate this issue with more effective therapies and in larger, sufficiently powered samples.

Until we know how the associations between depression and (subclinical) CVD come about in terms of physiological pathways, the best advice appears to be to focus on general cardiovascular risk reduction in high-risk populations. With respect to pharmacologic treatment in chronically depressed patients, extra caution taken by psychiatrists potentially could prevent the occurrence of some cardiovascular events. Before and during the start of treatment with especially TCAs and SNRIs, it now is common practice to screen for CVD by measuring blood pressure and performing an ECG in patients with cardiovascular risk factors and in elderly patients. In view of the available evidence as discussed in the former paragraphs, there are reasons to belief that a broader range of people might benefit from more active cardiovascular screening. For some subgroups (such as older patients with a chronic depression or with both depressive and anxiety disorders) regular measurements of blood pressure, cholesterol and glucose levels could be incorporated as a matter of standard practice. In addition, because of the increased prevalence of (subclinical) CVD in this population, extra attention to a healthy lifestyle appears an important aspect of the treatment of depressed patients. As to the primary target of cardiovascular risk intervention, the American Heart Associations has stated:

"Adoption of healthy life habits remains the cornerstone of primary prevention, including the avoidance of tobacco (including second-hand smoke), healthy dietary patterns, weight control, and regular, appropriate exercise. An important role of healthcare providers is to support and reinforce these public health recommendations for all patients." (Pearson *et al.* 2002)

Regarding exercise, some inspiring observations for the improvement of both mental and vascular health have recently been published: physical activity reduces the risk of CVD events (Hamer *et al.* 2011) and positively influences depressive complaints (Carek *et al.* 2011; Hoffman *et al.* 2011). The reinforcing and supporting role thus also fits professionals in the field of chronic depression, particularly since a tendency to ignore cardiovascular symptoms and taking action from it might be inherent in serious mental illnesses.

## **Author details**

288 Psychiatric Disorders – New Frontiers in Affective Disorders

chronic psychopathology.

samples.

**4. Possible implications**

2010), including abdominal obesity, lipid abnormalities, hypertension, and hyperglycaemia. Based on a community sample of older persons, (Vogelzangs *et al.* 2011) found that depressed subjects with metabolic syndrome ('metabolic depression') were almost 3-fold more likely to have persistent or recurrent depression. In addition, depression and more specifically treatment resistant depression has been associated with inflammation (Miller *et al.* 2009). Since inflammation is considered one of the important mechanisms that enhance the development of CVD (Willerson & Ridker, 2004), individuals who are nonresponsive to antidepressant treatment may have a higher likelihood of future cardiovascular events. Furthermore, specific types of antidepressant medications (e.g. TCAs and SNRIs) have been associated with unfavourable side-effects on metabolism, sympathetic activity and the immune system (Licht *et al.* 2012; van Reedt Dortland *et al.* 2010; Vogelzangs *et al.* 2012). Although the prospective nature of some evidence suggests that active ingredients of the antidepressants might be responsible (Licht *et al.* 2012), it also is likely that patients who use these antidepressants differ from non-users or SSRI users by having more severe and more

The above reviewed epidemiological evidence seems to indicate that chronic depression can be considered a cardiovascular risk factor. The question now arises of how this knowledge may be useful in clinical practice. First, modification of the risk factor would be expected to have beneficial effects on vascular health. Apart from the challenge this by definition means in chronic depression, it is still unknown whether successful treatment of depression indeed leads to improvement in cardiovascular morbidity and mortality. As for now, randomized controlled trials in CVD-free populations have not yet been carried out. Some trials (SADHART, (Glassman *et al.* 2002); ENRICHD, (Berkman *et al.* 2003); MIND-IT, (van Melle *et al.* 2007)) did investigate the effects of antidepressant psychotherapy or pharmacotherapy on cardiovascular morbidity and mortality in coronary patient populations. Although these studies have shown that depression is treatable in coronary patients, no significant differences were found in medical end-points between intervention and control groups. However, (Carney & Freedland, 2007) have pointed out that future studies are still needed to reinvestigate this issue with more effective therapies and in larger, sufficiently powered

Until we know how the associations between depression and (subclinical) CVD come about in terms of physiological pathways, the best advice appears to be to focus on general cardiovascular risk reduction in high-risk populations. With respect to pharmacologic treatment in chronically depressed patients, extra caution taken by psychiatrists potentially could prevent the occurrence of some cardiovascular events. Before and during the start of treatment with especially TCAs and SNRIs, it now is common practice to screen for CVD by measuring blood pressure and performing an ECG in patients with cardiovascular risk factors and in elderly patients. In view of the available evidence as discussed in the former paragraphs, there are reasons to belief that a broader range of people might benefit from more active cardiovascular screening. For some subgroups (such as older patients with Adrie Seldenrijk, Nicole Vogelzangs, Patricia van Oppen, Brenda Penninx and Anneke van Schaik *Department of Psychiatry, Vrije Universiteit, Amsterdam, Netherlands*

## **5. References**

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**Section 5**

**Challenging the Stigma of Serious Mental Illness**

**Challenging the Stigma of Serious Mental Illness**

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**Chapter 14**

© 2013 Renes, licensee InTech. This is an open access chapter 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.

© 2013 Renes, licensee InTech. This is a paper 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.

Saks is the Associate Dean, Chaired Professor of Law, Psychology, and Psychiatry & Behavioral Sciences at the University of Southern California Gould School of Law; Adjunct

**A Journey Through Schizophrenia**

Schizophrenia rolls in like a slow fog, becoming imperceptibly thicker as time goes on. At first, the day is bright enough, the sky is clear; the sunlight warms your shoulders. But soon, you notice haze beginning to gather around you, and the air feels not quite so warm. After awhile, the sun is a dim lightbulb behind a heavy cloth. The horizon has vanished into a gray mist, and you feel a thick dampness in your lungs as you stand, cold and wet, in the

The positive and negative symptoms and the prodromal, acute, and residual phases of schizophrenia are described in this chapter using the personal accounts of Elyn Saks and other professionals who have made public their personal struggles with schizophrenia. Psychologists, psychiatrists, and other professionals have disclosed their stories in the professional literature and their own biographies. These professionals believe there is a need for the general public and those with serious mental illnesses to hear stories of those who are leading successful lives after surviving the fire of the illness and its treatment (Bassman, 1997; Baxter, 1998; Breeding, 2008; Deegan, 1993; Deegan, 2003; Freese, Knight, & Saks, 2009). The successes reported by these professionals are not anomalies. Longitudinal studies report a large number of people with schizophrenia seeing improvement in their condition over time (Davidson, Schmutte, Dinzeo, & Andres-Hyman; 2008; Ellison, Russinova, Massaro, Lyass, 2005; Siebert, 2005). These individuals also make the case for the need of those with schizophrenia and other mental illnesses to be heard by professionals who offer understanding, hope, and support and listen with an understanding heart rather than from an uncaring, objective perspective (Brooks, 2011; Chadwick, 2006; Deegan, 1993; Frese et al.,

Additional information is available at the end of the chapter

Susan L. Renes

**1. Introduction**

http://dx.doi.org/10.5772/53225

afternoon dark. (Saks, 2007, p. 35).

2009; Frese & Davis, 1997).

**2. Prodromal phase**

## **A Journey Through Schizophrenia**

Susan L. Renes

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53225

## **1. Introduction**

Schizophrenia rolls in like a slow fog, becoming imperceptibly thicker as time goes on. At first, the day is bright enough, the sky is clear; the sunlight warms your shoulders. But soon, you notice haze beginning to gather around you, and the air feels not quite so warm. After awhile, the sun is a dim lightbulb behind a heavy cloth. The horizon has vanished into a gray mist, and you feel a thick dampness in your lungs as you stand, cold and wet, in the afternoon dark. (Saks, 2007, p. 35).

The positive and negative symptoms and the prodromal, acute, and residual phases of schizophrenia are described in this chapter using the personal accounts of Elyn Saks and other professionals who have made public their personal struggles with schizophrenia. Psychologists, psychiatrists, and other professionals have disclosed their stories in the professional literature and their own biographies. These professionals believe there is a need for the general public and those with serious mental illnesses to hear stories of those who are leading successful lives after surviving the fire of the illness and its treatment (Bassman, 1997; Baxter, 1998; Breeding, 2008; Deegan, 1993; Deegan, 2003; Freese, Knight, & Saks, 2009). The successes reported by these professionals are not anomalies. Longitudinal studies report a large number of people with schizophrenia seeing improvement in their condition over time (Davidson, Schmutte, Dinzeo, & Andres-Hyman; 2008; Ellison, Russinova, Massaro, Lyass, 2005; Siebert, 2005). These individuals also make the case for the need of those with schizophrenia and other mental illnesses to be heard by professionals who offer understanding, hope, and support and listen with an understanding heart rather than from an uncaring, objective perspective (Brooks, 2011; Chadwick, 2006; Deegan, 1993; Frese et al., 2009; Frese & Davis, 1997).

## **2. Prodromal phase**

Saks is the Associate Dean, Chaired Professor of Law, Psychology, and Psychiatry & Behavioral Sciences at the University of Southern California Gould School of Law; Adjunct