While not an issue for Service user 12, he again seemed to associate mental illness more generally with decreased strength or determination:

"I am a very strong minded person even though I have mental illness and all...I'm very strong minded in the sense if I say I'm starting Monday, no smoking. I will start Monday and there'll be no smoking." [Service user]

In general, he seemed to need the assistance of the programme less with a clear focus on his own plan and preparation. This contrasted with Service users 18 and 14 whose reports suggested they wanted or needed more external pressure to quit or set a date:

"People like that, facilitators need to give me a good boot in the backside, and say, "[Name] get in there and buy them patches." [Service user]

"I would have like that they pinpoint a bit more out on stop the smoking. It's to stop smoking and they don't do that either there, you know, they are very careful with not to say that [you have to stop smoking], you know. . . and I find that amazing that they don't, even a cessation group, they don't do that either, you know. I think I need that. I think I need that somebody says to me you stop smoking now." [Service user]

Service user 14 did go on to state however, that she would prefer to be given a quit date in the future rather than told to stop straight away:

"I'd rather have a date in the future so that I can get used to it, you know" [Service user]

### **Smoking among peers and past culture**

The prevalence of smoking among people with MHDs may also represent a barrier given the culture of smoking this creates among peers.

There was also some evidence of this increased prevalence and a culture of smoking at EVE centers:

"You get shanghaied into going out for a cigarette. . . ah no there's, there's one or two that smoke here and if they go outside, they'll give you a cigarette and you have one." [Service user]

Centers also experience issues such as a culture of money lending and borrowing to buy cigarettes;

"One other thing, em, came up there, just thinking em, people who smoke like that financially they don't have as much money, so that, there was a knock on effect so they wouldn't have as much money and like [Facilitator 2] said they'd do anything to get a cigarette so borrowing became an issue. . . and as a result there's problems then people are not giving back the monies so there was huge knock on effects from that." [Facilitator]

as well as trading of counterfeit cigarettes;

"and then the dodgy ones as well, a guy going in [to town] buying them, and I've seen it in centers, coming in on Monday with like 200 cigarettes and doling them out." [Facilitator]

Other reports however contradicted this and overall there was a sense the culture of smoking was waning:

"Smoking has kind of died down here." [Service user] "I think it was a lot higher when I first started. This is even well before smoking cessation and now it's, I'd say we're twenty, twenty percent maybe smoking twenty-five maybe." [Facilitator]

Facilitators commented on the lower prevalence among younger service users;

"There was a culture of go and have a cigarette I think going back but that's definitely not the case with the younger people coming in. I don't think we have as many smokers definitely with the younger em variety." [Facilitator]

while for some the past culture of smoking also seemed to serve as an extra motivator to provide support now:

"We have a responsibility to address this I believe, because our services have condoned this for so long and the medical community probably exacerbated it over the years, made it worse so we have a responsibility to kind of, maybe be a little more of campaigners about it." [Facilitator]

### **Lifestyle: lack of structure/activities**

Inactivity, lack of structure and time spent alone emerged as particular barriers for service users from both facilitators and service user perspectives. Service users discussed inactivity, boredom, time alone and filling a vacuum as prompts to smoke:

Interviewer: And if I was to ask you why did you smoke, what would you say?

Service user 7: Em, I'd say the vacuum after I got sick, and being off work, having that time on my hands.

This was mirrored in the accounts of several facilitators, who also noted a lack of structure and time alone as key barriers for individuals with MHDs.

Hobbies, work, and being otherwise busy often emerged as distractions;

"There are places I smoke less. Yeah. When I'm doing something I get it done, you know" [Service user]

Service user 15 referred to the years when he stopped smoking as partially down to being busy with work;

"Well I was working away like and there was no point to be smoking while you were working, you know, I'd be stopping every 5 min if I had of been smoking at the time, so it helped me as regards work as well." [Service user]

while Service user 12 described how his hobby serves as a powerful distraction;

"I smoke an awful lot less when I'm gigging" [Service user] There were calls from service users and facilitators for more activities;

"I think someone mentioned it, just in terms of structure I think structure is, if a person's day can be filled and it doesn't matter whether it's you know within the center, outside the center, in terms of leisure activities and social activities, that's obviously going to help in in a big way" [Facilitator]

and some felt there was a need in particular for specific replacement activities though concrete suggestions were limited:

"What to do when they do give up cigarettes. I found like, I started doing myself knitting and reading more and doing things like that, I think something like that could be put into the book, what to do, [murmuring] ideas and suggestions. . . I feel what we need to do is encourage people to change their lifestyle, I think that would help an awful lot." [Facilitator and Former Smoker]

"Something to do with their hands, you know, knitting or sewing or something like that. . . but my, my hands shake so it's very difficult for me to, to do things." [Service user]

### **MHDs as an excuse rather than an actual barrier**

There was also some suggestion from facilitators that in some cases, MHDs can act as an excuse at the individual level rather than a barrier in terms of actual ability to quit smoking. This is perhaps unsurprising given the past culture discussed above.

"I think there can be some people who might use their, their mental health as an excuse. . . they might be in a system where they might have a nurse or a key worker who is facilitating and done a lot for them and now they're signed up to a smoking cessation programme but now it's them that has to do it, nobody else is going to quit for them." [Facilitator]

Facilitator 7 addressed this by highlighting the equality between service users and staff;

"I've used me as an example in my groups 'So you're different to me because you have a MHD? Nah you're no different to me you're able to do loads of things I can't do. . . so if you I think if we hit it at that level and then all of a sudden they're looking at you and they start laughing, they know straight away, they're like alright I'm not gonna use that." [Facilitator]

which is also central to the structure and ethos of the service more generally.

### **Timing**

While many felt MHDs can indeed make quitting harder facilitators felt timing can be a really important factor as a barrier to attending the programme at all;

"The interesting thing about the first session was that the person, it was Christmas time it was the wrong time and they found by, I think we got to week 5, they found that week 5 they had to stop because their cigarette smoking had increased! Because of Christmas and stresses and all that kinda thing and all so" [Facilitator]

but also to actual quitting in those that did attend:

"I did the course 3 times in [name of location] and she sat on each one of them, but she had something going on in her life that she just wasn't ready and...it was a bit her mental health was a bit unstable at the time, yeah and she had family issues she had to get sorted out and she just felt she needed that cigarette." [Facilitator].

**Table 2** summarizes the sub-theme MHD barriers discussed in this paper providing further sample quotes.

## DISCUSSION

This study aimed to identify key enablers of, and barriers to, the implementation of a quit smoking programme in community adult mental health services. By exploring an ongoing group smoking cessation intervention in a real world mental health setting, from both facilitator and service user experiences of its implementation, this study filled an important gap in knowledge.

The emergence of health and money as important motivators is consistent with previous research in relation to the enablers of smoking cessation among individuals with severe mental illness (37, 38), and is similar to other populations (39–41). The use of carbon monoxide monitors makes use of biofeedback, which is arguably one of the strongest behavior change techniques (42), and appeared to be a powerful, and appropriate, aspect of this programme also, spurring cessation efforts as well as reinforcing those already quit. Interestingly however the monitor also appeared to vindicate the use of e-cigarettes in service user's eyes, presumably an unintended consequence given the HSE have not endorsed e-cigarettes as a cessation aid (43).

The emergence of facilitator resourcefulness and tailoring of the programme to individuals' needs as an enabler is consistent with previous studies among mental health patients. These studies found flexible, personalized and responsive approaches to be helpful with benefit emphasized by both facilitators and service users (30, 44). Notably, this flexible, individualized approach is also consistent with the person-centered philosophy underpinning delivery of EVE programmes in general. An active, open and engaged recruitment approach seemed to work best as opening up to those not ready to quit, but interested in attending, sometimes led to unexpected wins by spurring on later quit attempts. Non-voluntary attendance without personal goals however appeared to lead to disengagement, frustration for both service users and facilitators and potentially affected overall group atmosphere.

The recently introduced Tobacco Free Campus Policy emerged as both an enabler and barrier to programme implementation and participant quitting. The identification of the partial nature of the ban and its varying implementation as barriers supports other studies which show partial smoke-free policies are less successful than total smoke-free policies. A partial ban creates additional problems and has a limited impact on the staff and service user culture of smoking (45). Moreover, the timing of implementing cessation support, following or alongside the introduction of a smoke-free campus policy, may have negatively affected morale.

Conflicting priorities and a lack of prioritizing smoking cessation support as part of staff workload has previously emerged as a barrier among HCPs in Ireland and internationally (46–48). As well as in relation to mental health services more specifically especially in the context of outpatient settings (38).

The emergence of the current lack of a joined-up approach as a barrier producing inconsistencies in relation to lack of cessation supports and also in relation to exemptions from tobacco free policies echoed the conclusions of a recent review of qualitative studies which called for cessation to be addressed at all levels (systemic, health provider, and individual) among people with severe mental illness (37). Although there is a lack of evidence relating to the effectiveness of advice for those with serious or severe mental illness (49, 50), the motivational impact of HCP advice, where it did occur, was important. This is not surprising, given prompts from health professionals have been shown to be an important driver in quit attempts among smokers in general (51–53).

In line with previous research, barriers relating to MHDs including smoking as a coping mechanism (44, 54–57); lack of self-belief (29, 54, 56); lack of consistent motivation (30, 38, 44); prevalence of smoking among peers and the culture within mental health settings (37, 44, 58); and lack of structure or alternative activities (59–61), also emerged from the data. Timing was also perceived to be an important factor by facilitators and some service users felt an inpatient stay was the wrong time for cessation. Evidence is still however lacking in this area due to the ongoing tendency for smoking cessation studies to recruit from psychiatrically stable rather than acutely unwell populations (50, 62).

## Implications

There was some evidence in the current study, of knowledge among service users and facilitators of the ineffectiveness of smoking as a coping mechanism and the ability of those with MHDs to quit. Overall, however, findings suggest that integrating education on the proven ability of people with MHDs to quit smoking, and the benefits of quitting for mental health, into facilitator training and resources for service users could be beneficial. It is also crucial that the service continue to present this opportunity to quit on an ongoing basis, especially given the accounts of non-attenders who also expressed the wish that this service remain as they may use it in future.

A stronger focus on replacement coping mechanisms and activities may be needed. It is important however to ensure these replacements are healthy. Given the increased physical health risks in general seen among those with MHDs (4, 63), the introduction of well-intentioned replacements such as biscuit breaks seem ill-advised. Rather, a focus on overall wellness and combining smoking cessation with broader health initiatives, a proven enabler, should continue; as should the open recruitment of those not ready to quit but interested in attending and perhaps cutting down. In light of the potential changing levels of motivation among those with MHDs, which were also reported in the current study, Williams and Ziedonis have previously recommended reduction toward abstinence as a method of harm reduction (64). Smoking cessation support should also ideally be in place in advance of the introduction of any new smoke-free policies. Appears that the introduction of a smokefree policy alone is insufficient. Appropriate implementation by enthusiastic staff with environmental barriers addressed in advance is required.

Finally, attending the cessation programme and attempting to quit turned out to be a longer and more circular process than anticipated for some, providing support for the idea that some individuals with MHDs may require more intensive, modified or tailored cessation support (25, 37, 65). It is important to note however that some service users in the current study needed little support to quit particularly in the early stages of implementation. Perhaps the introduction of new smoking policies and a support programme produce quick initial gains or "low-hanging fruit" in terms of the quitting of more motivated and less dependent smokers after which those more dependent smokers, needing greater support, remain. Regardless, there was a clear need to sufficiently equip facilitators, through enhanced training, guidelines or a nominated support contact, for attendees or groups getting "stuck" in order to avoid feelings of uncertainty and frustration. Beyond a support person, a forum for facilitator communication and collaboration could also be beneficial in sharing knowledge and approaches to obstacles.

Future research may wish to explore how the provision of evidence of successful smoking cessation in those with MHDs, as well as a greater focus on replacement coping mechanisms and activities, might enhance a smoking cessation programme for this population. Studies which include exploration of experience of use at both participant and provider levels in addition to cessation outcomes would be particularly useful.

## Strengths and Limitations

This study was strengthened by the participation of a high number of service users across a large number of the eligible centers as well as the inclusion of almost all facilitators, meaning results should have good external validity. Including the 16 sites meant contextual factors were well accounted for and barriers and enablers that emerged were truly cross-site. Previous qualitative studies of smoking cessation and other lifestyle interventions in individuals with serious or severe mental illness have at times involved very small samples of service users (66, 67), while others have failed to include the service user voice at all (38, 44).

Beyond the inclusion of both voices, the triangulation of sources, combining both service user and staff perspectives and experiences, also serves to validate study findings (68), adding credibility and strengthening confidence in the conclusions drawn (69). Lambert et al. have also found that the integration of focus group and interview data in particular, assists in the identification of individual and contextual circumstances, thus adding to interpretation and ultimately enhancing trustworthiness of results (70). The two-phase sequential design also allowed for the refinement of the facilitator focus group interview guide and thus allowed service users to set the agenda somewhat before facilitator data collection commenced. Unfortunately, due to incomplete data collection by staff, quantitative data on programme outcomes were unavailable so we were unable to include a mixed methods triangulation element to the data.

As this was a qualitative study, findings are not generalizable beyond the study population and conclusions drawn refer to the sample itself (71). Practical issues around staff availability led to pragmatic decisions including conducting a focus group with just two members and allowing a facilitator to join another focus group late. The recruitment of participants through HSE staff may have meant they did not believe the researcher was truly neutral and interview data confidential, although this was restated at the beginning of each interview and focus group, it is unclear if this affected findings.

## CONCLUSIONS

A group-based smoking cessation programme with an open recruitment approach and the provision of individual support, where needed, appeared to work well in community mental health services. Findings indicated that implementation of cessation programmes in community mental health settings may be best when done in advance of new tobacco free policies, when it is prioritized and sustained and when the cessation care provided also addresses the key barriers perceived as specific to those with mental health difficulties. More broadly, a joined-up approach across the health service seems necessary to address ongoing inconsistencies and support those with MHDs in their efforts to quit.

## AUTHOR CONTRIBUTIONS

AB designed the research instruments, completed all data entry and data analysis and wrote the manuscript as part of her PhD. JS provided feedback on research instruments, supervised AB in the conduction of thematic analysis and assisted in review of the current paper. LC provided feedback on research instruments, supervised AB in completing the study and assisted in review of the current paper. MW, GS, and TO'B provided original research ideas, designed the protocol and applied for research ethics approval, contributed to the design of research instruments and assisted in review of the current paper. DR contributed to the

## REFERENCES

data analysis of the manuscript, and assisted in review of the current paper. FD was the principal investigator for this project. He supervised the project, provided feedback on the design of research instruments, qualitative analysis and assisted in review of the current paper. All authors revised the original manuscript and provided critical input.

## FUNDING

This research was funded by the Health Research Board SPHeRE/2013/1 and the Health Service Executive EVE programme.

## ACKNOWLEDGMENTS

The authors would like to greatly thank Ms Pam McKay as well as all EVE center managers, QSP facilitators and service users for their assistance, support and participation throughout this study.

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2018 Burns, Webb, Stynes, O'Brien, Rohde, Strawbridge, Clancy and Doyle. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Stop Turning a Blind Eye: Tobacco Smoking Among Egyptian Patients With Schizophrenia

Hussien Elkholy <sup>1</sup> \*, Nahla Nagy <sup>1</sup> , Ghada R. A. Taha<sup>1</sup> , Mahmoud Elhabiby <sup>1</sup> , Mostafa Yosef <sup>2</sup> and Lobna Azzam<sup>1</sup>

<sup>1</sup> Neurology and Psychiatry Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt, <sup>2</sup> Community Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Background: Patients with schizophrenia have considerably higher rates of mortality than general population. Multiple factors may play a role in this. Despite being a major preventable cause of death, smoking is usually overlooked when dealing with patients with schizophrenia. Understanding the pattern of smoking, its severity, and the reasons to quit might be helpful in managing patients with schizophrenia and decreasing the mortality gap.

#### Edited by:

Andrea Fiorillo, Università degli Studi della Campania "Luigi Vanvitelli" Naples, Italy

#### Reviewed by:

João Mauricio Castaldelli-Maia, Faculdade de Medicina do ABC, Brazil Camilla Callegari, Università degli Studi dell'Insubria, Italy

> \*Correspondence: Hussien Elkholy<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Psychosomatic Medicine, a section of the journal Frontiers in Psychiatry

Received: 29 July 2018 Accepted: 03 December 2018 Published: 04 January 2019

#### Citation:

Elkholy H, Nagy N, Taha GRA, Elhabiby M, Yosef M and Azzam L (2019) Stop Turning a Blind Eye: Tobacco Smoking Among Egyptian Patients With Schizophrenia. Front. Psychiatry 9:703. doi: 10.3389/fpsyt.2018.00703

Subjects and Methods: The study included smokers divided into two groups; the first included 346 patients with schizophrenia while the second group had 150 smokers with no mental illness. Both groups were assessed and compared regarding sociodemographic variables, pattern of smoking, severity of nicotine dependence, and motivation to quit smoking.

Results: Earlier age of starting to smoke, higher number of cigarettes per day, and lower dependency scores were noted in patients with Schizophrenia. Positive correlation was found between positive symptoms and severity of dependence. Specific positive symptoms were correlated to number of cigarettes per day and time before first cigarette. Patients with Schizophrenia showed a significant difference in intrinsic reasons to quit (health concerns and self-control), which were also positively correlated to their positive symptoms score. Linear regression analysis for predictors of FTND score revealed that only age, sex, and schizophrenia were significant predictors of FTND score.

Conclusion: Patients with schizophrenia smoke at earlier ages and smoke more cigarettes per day, yet, have less severe dependence than non-schizophrenic counterparts. Positive symptoms play a role in their smoking pattern and severity. Health concerns and self-control are their main motives to quit smoking.

Keywords: tobacco smoking, nicotine, schizophrenia, motivation to quit, mortality, positive symptoms, PANSS

## INTRODUCTION

Mortality gap in schizophrenia is a significant issue (1). Physical illness is associated with the problem, which may be related to the adoption of unhealthy lifestyle behaviors (2).

Smoking is one of the main factors adding to the mortality gap in patients with schizophrenia being one of the leading causes of premature mortality in them (3). Yet, it is usually overlooked. Tobacco smoking is common in schizophrenia (4). Patients with schizophrenia have high reported smoking rates of 58–90% (5). This is considerably higher than smoking rates of 24% in the general public (6) and of ∼50% in people with other psychiatric diagnoses (7). Patients with schizophrenia are not only more likely to smoke, but also smoke more heavily, have longer smoking duration, and have lower rates of cessation compared to individuals without schizophrenia (8). Among different factors that may explain the high rates of smoking among patients with schizophrenia is the shortage of smoking cessation services in mental health treatment programs (9).

Smoking is a major preventable cause of death (10). In patients with schizophrenia, the risk of mortality is doubled, and the risk of cardiac-related morality is increased about 12-fold in smokers compared to non-smokers (1, 11). However, despite the high frequency of smoking in schizophrenia, little is known about clinical correlates or pharmacological treatments associated with tobacco smoking in patients with schizophrenia (12).

The relation between schizophrenia and smoking has been the subject of many studies for years. Some showed smoking to be associated with both positive and negative symptoms of schizophrenia, others found relationship with just one of these domains (13), while some found no relationship with either (14). Some authors suggest that Schizophrenia does not only increase the possibility of smoking but increases the risk of severe smoking as well (15).

Consequently, the high rates and severer patterns of smoking in patients with schizophrenia are suggested to contribute to reduction in life expectancy and to excess morbidity and mortality among them. Moreover, cigarette smoking has also been demonstrated to be associated with more frequent hospital readmissions, increased financial burden, and higher rate of attempted suicide (16). Addressing several factors like lack of resources, smoking, physical illness, and lifestyle modification may help decreasing the mortality gap in schizophrenia (1).

On the other hand, studies suggest that patients with schizophrenia are at least as motivated to quit as the general population but have lesser chance to quit attempts (17, 18). Moreover, several studies suggest that tobacco dependence treatment is effective in patients with mental illness (9, 19, 20), with some exploring the safety and efficacy of pharmacological treatment in this group (21, 22). Despite that, most psychiatric services do not address smoking cessation in patients with schizophrenia. This may be due to the lack of a consensus on certain recommendations to treat tobacco dependence in this patients group. Moreover, only modest results are achieved with the available regular approaches for smoking cessation (23). However, specific programs that promote healthy living, e.g., LIFESTYLE trial (2) are emerging recently. Those programs might play a key role in helping patients with Schizophrenia getting rid of harmful habits like smoking which might decrease mortality rates.

Therefore, as smoking appears to be one of the major factors contributing to the mortality gap in patients with schizophrenia, this study aims at shedding the light on smoking patterns among a sample of patients with Schizophrenia in Egypt and to highlight the patients' willingness to quit.

## MATERIALS AND METHODS

This is a comparative cross-sectional study between two different groups; the first included smokers with schizophrenia and the second had smokers without mental illness. The sample was a convenient sample collected over a 1-year period. The sample size was also calculated prior to the study using PASS version 15.0, setting the power at 80% and the significance level (α- error) at 0.05, to make sure the study reaches the minimal sample size. Data from previous study (24) reported that the mean immediate reinforcement score for patients with schizophrenia was 2.0 ± 1.1 compared to 2.3 ± 0.9 for normal controls. Calculation according to these values produced a minimal sample size of 139 subjects per group, rounded to 150 in each.

The first group; included 346 patients with schizophrenia who were collected during the study period using a convenient sampling method. Patients fitting the inclusion criteria were approached in both inpatients and outpatients departments, at the Institute of Psychiatry, Faculty of Medicine, Ain Shams University, and those who consented were included. This group included both sexes, older than 18 at the time of the study, with the diagnosis of Schizophrenia according to DSM IV-TR criteria and had been smokers for at least 12 months. Presence of any other Axis I psychiatric diagnosis was an exclusion criterion.

As for group two; 150 subjects were recruited from the smoking cessation clinic and we also called for volunteers from employees and students through an announcement in the university hospitals. This group included both sexes, above the age of 18 with exclusion of those with any Axis I psychiatric disorder.

Required ethical approvals were obtained prior to the study. Informed written consents were requested from all participants, including detailed description of the study procedures. Sociodemographic data were collected using a questionnaire based on the admission sheet of the Institute of Psychiatry, Ain Shams University.

Further assessment was done using the following. (a) Structured Clinical Interview for DSM-IV Axis-I disorders (SCID) (25), an Arabic version validated in Egyptian studies was used (26) to confirm the diagnosis of Schizophrenia and to exclude other Axis I psychiatric disorders in both groups. (b) Positive and Negative Syndrome Scale (PANSS) (27). The Positive and Negative Syndrome Scale is one of the most widely used methods for standardized measurement of schizophrenic core symptoms. The PANSS consists of 7 positive symptom items, 7 negative symptom items, and 16 general psychopathology items. All 30 PANSS items are rated on a 7-point symptom severity scale, ranking from 1 (absent) to 7 (extremely severe). (c) Fagerström Test for Nicotine Dependence (FTND) Arabic version which has been validated for use among Arabic speaking population (28). In this study, nicotine dependence was classified into two categories; low dependence (LD; FTND < 4) and high dependence (HD; FTND ≥ 4). (d) Reasons for Quitting scale (RFQ) (29), which gathers information about motivations and reasons of smokers to quit smoking. The RFQ is composed of 20 self-report items and measures intrinsic and extrinsic motivation for quitting smoking. It consists of two intrinsic motivation subscales, self-control (e.g., "To show myself I can quit if I really want to") and health concerns (e.g., "Because I'm concerned that smoking will shorten my life"), and two extrinsic motivation subscales, immediate reinforcement (e.g., "To save money that I spend on cigarettes") and social pressure (e.g., "Because someone has given me an ultimatum to quit").

The collected data was revised, coded, tabulated, and introduced to a PC using Statistical package for Social Science (SPSS 20). Data was presented, and suitable analysis was done according to the type of data obtained for each parameter.

i Descriptive statistics:

	- 1. Student T-Test was used to assess the statistical significance of the difference between two study group means.
	- 2. Chi-Square test was used to examine the relationship between two qualitative variables.
	- 3. Correlation analysis (using Pearson's and Spearman's methods): To assess the strength of association between two quantitative variables. The correlation coefficient denoted symbolically "r" for Pearson correlation and "rs" for Spearman correlation defines the strength (magnitude) and direction (positive or negative) of the linear relationship between two variables.
	- 4. Linear regression was used to test and estimate the dependence of a quantitative variable based on its relationship to one or more independent variables.

 The mean age of the group with schizophrenia was 33.28 years (±9.57 SD) and for the other group 36.97 years (±10.52 SD). The levels of illiteracy (13.9%) and unemployment (21.7%) were higher among patients with schizophrenia than in non-schizophrenia group (0.7 and 6.7%, respectively) (**Table 1**).

As regard patients' symptoms profile, they had higher positive scale scores (Mean ± SD = 25.01 ± 5.08) than negative scale scores (Mean ± SD = 18.64 ± 8.05).

## Pattern of Use and Severity of Tobacco Dependence Among Patients

Comparing the two groups, a statistically significant difference in the age of starting smoking was detected as the patients started at an earlier age than the other group (mean: patients with schizophrenia 22.15 ± 6.17 SD, non-schizophrenics 23.93 ± 5.89 SD, p = 0.003). However, patients with schizophrenia had statistically significant lower dependency scores using FTND (cases 6.6 ± 1.56, controls 7.12 ± 1.43, p = <0.001) (**Table 2**).

The number of cigarettes per day was significantly (P < 0.001) higher among patients group as 39.9% of patients with schizophrenia smoked more than 20 cigarettes per day compared to only 20.6% of the group without schizophrenia. Moreover, patients preferred their first cigarette within 5 min of awakening (39%) compared to the other group (14.7%) (P < 0.001).

On the other hand, there is a statistically significant negative correlation (r = −0.158) between positive scale score and age of starting smoking (the younger the age of start smoking, the higher the positive scale score), and a statistically significant positive correlation between positive scale score and FTND score (r = 0.246) (the higher the FTND score, the higher the positive scale score). This suggests that patients with more positive symptoms start smoking early and have more dependency score on FTND. However, no significant correlations were detected with negative scale and general scale scores (**Table 3**).

Upon performing linear regression analysis for predictors of FTND score, it was revealed that only age (0.041, 95% CI: 0.03– 0.05), sex (−0.917, 95% CI: −1.18 to −0.65, ref. male), and schizophrenia (−0.398, 95% CI: −0.69 to −0.1) were significant predictors of FTND score (**Table 4**). Moreover, in the patients group, linear regression analysis for predictors of FTND score revealed that only age (0.043, 95% CI: 0.03–0.06), sex (−1.145, 95% CI: −1.45 to −0.84, ref. male), positive score (0.11, 95% CI: 0.08–0.14), and negative score (0.041, 95% CI: 0.02–0.06) were significant predictors of FTND score (**Table 5**).

Moving to specific symptoms, this study found statistically significant positive correlation, between number of cigarettes and severity of delusions, conceptual disorganization, hallucination, excitement, hostility, anxiety, preoccupation, and poor impulse control and statistically significant negative correlation with motor retardation and poor attention (**Table 6**).

Regarding correlation between symptomatology and time spent before the first cigarette, this study found statistically significant negative correlation between time spent before the first cigarette and severity of delusions, conceptual disorganization, hallucination, excitement, persecution, hostility, somatic concern, anxiety, preoccupation, and poor impulse control. While a statistically significant positive correlation was found with motor retardation (**Table 6**).

## Reasons for Quitting

Assessing the reasons for quitting, significant differences in intrinsic reasons were detected. This includes "health concerns" (mean: patients group 2.63 ± 1.02, non-schizophrenic group 2.17 ± 1.13) with a P-value of <0.001 and "self-control" (mean: patients group 1.92 ± 1.06, non-schizophrenic group 1.69 ± 0.88) with a P-value of 0.017. Patients with schizophrenia were more concerned with health risk and to gain self-control over smoking than their counterparts from the other group. However, no statistically significant differences were detected as regard extrinsic factors; immediate reinforcement and social pressure as reasons to quit.

Moreover, regarding PANSS positive scale score, statistically significant positive correlation with health concern subscale and

TABLE 1 | Comparison between smokers with schizophrenia and smokers with no mental illness regarding socio-demographic data.

TABLE 2 | Comparison between smokers with schizophrenia and smokers with no mental illness regarding age, pattern of smoking and FTND score.

with self-control subscale were detected. On the other hand, negative correlations with immediate reinforcement subscale and social pressure subscale were also found. This suggests that patients with more positive symptoms are more concerned with intrinsic reasons (i.e., health and self-control) to quit smoking and less concerned with extrinsic reasons (i.e., less affected by immediate reinforcement and social pressure) (**Table 3**).

Furthermore, statistically significant positive correlation between general scale score and health concern subscale and negative correlation with immediate reinforcement subscale were detected. This implies that patients with schizophrenia who have higher scores on the general scale of PANSS are more concerned with health but less concerned with immediate reinforcement (**Table 3**).

## DISCUSSION

Schizophrenia is associated with mortality rates that are two to three times higher than the general population. The number of deaths due to cardiovascular disease is high and could be reduced by lifestyle modification (2, 30). Kelly et al. (11) reported a significant risk of increased mortality from smoking in patients with schizophrenia which was mainly evident in the middle ages (35–54 y). This implies the importance of a better understanding

TABLE 4 | Linear regression analysis for predictors of FTND score in both groups.

TABLE 5 | Linear regression analysis for predictors of FTND in patients with Schizophrenia.

of the smoking problem among patients with schizophrenia, and the inclusion of the assessment, and management of smoking in routine treatment strategies (9).

When assessing age of starting smoking, this study found that patients with schizophrenia start in a younger age, which may suggest that smoking might be involved in pathophysiology of schizophrenia or smoking may be an early sign of prodromal symptoms. A birth cohort study (31) links cigarette smoking to the prodromal phase of schizophrenia and suggested that impaired nicotinic neurotransmission is involved in the pathophysiology of schizophrenia. However, another study conducted by Wade et al. (32), reported that patients with schizophrenia began smoking around the same age as healthy controls, i.e., in their teenage years.

On the other hand, the current study found that patients with schizophrenia had lower dependency scores on FTND compared to the other group. A possible explanation for this is the high prices of cigarettes due to increased taxes especially in the recent years, which is a burden to the patients with schizophrenia who already suffer from financial problems. Another possible explanation is that most of patients with schizophrenia in Egypt live with their families who control their cigarettes supply. This result comes in concordance with several studies that indicated that nicotine dependence and the number of cigarettes per day are not higher and even sometimes similar to those without schizophrenia (33). However, other studies (3, 34, 35) found that people with schizophrenia are heavier smokers and had high levels of nicotine dependence scores.

The relation between smoking and positive and negative symptoms have always been debatable. Results of different studies have yielded various outcomes (4, 36, 37) with some reporting smoking related to positive symptomatology, to negative, to both positive, and negative symptomatology (38, 39) or to neither positive nor negative symptoms (37).

On assessing patients with positive symptoms, this study found that patients with more positive symptoms start smoking early and have more dependency score of FTND of cigarettes smoking. Yet, no significant correlations between negative symptoms or general symptoms severity and age of patients, age of start smoking, or cigarettes dependency were detected. This comes in concordance with work done by Ziedonis et al. (40) who found that heavy smokers (here defined as >25 cigarettes per day) had the most positive symptoms and a significantly lower number of negative symptoms. In addition, a cohort study done by Aguilar et al. (41) found that highly dependent smokers had the most severe positive symptoms of schizophrenia. Moreover, it was reported that tobacco use, and weight gain/obesity were associated with increased severity of symptoms of schizophrenia and decreased functioning (42).

However, upon performing linear regression analysis, both positive and negative scores were significant predictors of FTND score. This comes in concordance with study done by Patkar et al. (13) for assessments of nicotine dependence in relation to PANSS

TABLE 6 | Correlation between symptoms of schizophrenia (PANSS) and the number of cigarettes and time spent before first cigarette.

who found significant positive correlations between Fagerstrom scores and the total negative symptom score and scores on the negative symptom subscales of blunted affect, social withdrawal, difficulty in abstract thinking, and stereotyped while positive symptoms were not significantly associated with smoking.

On the other hand, morning smoking preference was positively correlated to conceptual disorganization and excitement in this sample. As regard the correlation with conceptual disorganization, this may be explained by the possibility that nicotine use enhances performance in several domains of cognitive functioning which may be reflected on process of thinking and goal-directed sequencing. Thus, morning smoking may be preferred because it might improve this thinking processing from the start of the day. The relaxing effect of nicotine may also explain the correlation between morning smoking and excitement (43). This study also linked the number of cigarettes and time spent before the first cigarette to certain symptoms including delusions, hallucinations, conceptual disorganization, excitement, hostility, anxiety, and poor impulse control.

When it comes to quitting, Evins et al. (44) observed that persons with schizophrenia are often highly motivated and persistent in their attempts to quit smoking despite having long histories of smoking. This study found that patients with schizophrenia are more concerned with intrinsic factors, i.e., heath risk and self-control as reasons to quit. These results are in concordance with a study done by Addington et al. (45) who found the chief reasons for quitting smoking in patients with schizophrenia could be health concerns, which ultimately reinforce these individuals to quit. However, this is not in concordance with other studies (46) which found that people with schizophrenia were significantly less likely to consider quitting for health concerns.

On correlating positive and negative symptoms with reasons for quitting, we found that patients with more positive symptoms are more concerned with intrinsic reasons (with health and selfcontrol) and less concerned with extrinsic reason (less affected by immediate reinforcement and less affected by social pressure). However, no significant correlation between negative symptoms and the subscales of reasons for quitting was detected.

## LIMITATIONS

The main limitation of the study is its non-generalizability. It included a not well-representative community sample; as the sample was only collected from Institute of Psychiatry, Ain Shams University Hospitals.

## CONCLUSION

Tobacco is one of the major contributors to major health issues in patients with schizophrenia. It seems that there is some sort of a link between some positive symptoms of schizophrenia and severity of tobacco dependence, number of cigarettes, and morning smoking preference. It also appears that patients with schizophrenia who have more severe positive symptoms are more inclined to quit smoking; mainly for health concerns. Thus, it is important for psychiatrists to investigate these issues when assessing patients with schizophrenia especially their readiness to quit. Addressing tobacco use during the course of treatment might have positive outcomes on schizophrenia and health related issues and consequently lead to decreased morbidities and mortalities.

## ETHICS STATEMENT

This study was carried out in accordance with the recommendations of the ethical committee of Faculty of Medicine, Ain Shams University. The protocol was approved by the ethical committee of Faculty of Medicine, Ain Shams University. All subjects gave written informed consent.

## AUTHOR CONTRIBUTIONS

NN, GT, ME, HE, and LA contributed to conception and design of the study. LA was the researcher responsible for the field work

## REFERENCES

and organized the database. MY revised all the collected data and performed the statistical analysis. HE collated all results and wrote the first draft of the manuscript. All authors contributed to the revision, read and approved the submitted version.

Textbook of Psychiatry. Philadelphia, PA: Lippincott Williams and Wilkins (2009). p. 1499–500.

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Elkholy, Nagy, Taha, Elhabiby, Yosef and Azzam. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Physical Exercise in Major Depression: Reducing the Mortality Gap While Improving Clinical Outcomes

Martino Belvederi Murri 1,2,3 \*, Panteleimon Ekkekakis <sup>4</sup> , Marco Magagnoli <sup>1</sup> , Domenico Zampogna<sup>1</sup> , Simone Cattedra<sup>1</sup> , Laura Capobianco<sup>1</sup> , Gianluca Serafini 1,2 , Pietro Calcagno<sup>1</sup> , Stamatula Zanetidou<sup>5</sup> and Mario Amore1,2

<sup>1</sup> Section of Psychiatry, Department of Neuroscience, Ophthalmology, Genetics and Infant-Maternal Science, University of Genoa, Genoa, Italy, <sup>2</sup> IRCCS Ospedale Policlinico San Martino, Genova, Italy, <sup>3</sup> Department of Psychological Medicine, King's College London, London, United Kingdom, <sup>4</sup> Department of Kinesiology, Iowa State University, Ames, IA, United States, <sup>5</sup> Department of Mental Health, Consultation Liaison Psychiatry Service, Bologna, Italy

#### Edited by:

Andrea Fiorillo, Università degli Studi della Campania "Luigi Vanvitelli" Naples, Italy

#### Reviewed by:

Alejandro Magallares, Universidad Nacional de Educación a Distancia (UNED), Spain Federica Pinna, Università degli Studi di Cagliari, Italy

#### \*Correspondence:

Martino Belvederi Murri<EMAIL_ADDRESS><EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Psychosomatic Medicine, a section of the journal Frontiers in Psychiatry

Received: 28 June 2018 Accepted: 20 December 2018 Published: 10 January 2019

#### Citation:

Belvederi Murri M, Ekkekakis P, Magagnoli M, Zampogna D, Cattedra S, Capobianco L, Serafini G, Calcagno P, Zanetidou S and Amore M (2019) Physical Exercise in Major Depression: Reducing the Mortality Gap While Improving Clinical Outcomes. Front. Psychiatry 9:762. doi: 10.3389/fpsyt.2018.00762 Major depression shortens life while the effectiveness of frontline treatments remains modest. Exercise has been shown to be effective both in reducing mortality and in treating symptoms of major depression, but it is still underutilized in clinical practice, possibly due to prevalent misperceptions. For instance, a common misperception is that exercise is beneficial for depression mostly because of its positive effects on the body ("from the neck down"), whereas its effectiveness in treating core features of depression ("from the neck up") is underappreciated. Other long-held misperceptions are that patients suffering from depression will not engage in exercise even if physicians prescribe it, and that only vigorous exercise is effective. Lastly, a false assumption is that exercise may be more harmful than beneficial in old age, and therefore should only be recommended to younger patients. This narrative review summarizes relevant literature to address the aforementioned misperceptions and to provide practical recommendations for prescribing exercise to individuals with major depression.

#### Keywords: depression, mortality, exercise, physical activity, efficacy, cardiovascular disease

## INTRODUCTION

Depression exerts an enormous impact on different domains of individual functioning, as well as physical health (1, 2). Physical exercise is increasingly recognized as an effective intervention to improve these outcomes.

Patients with major depression seldom receive adequate treatment. When they do, there is a high likelihood they remain depressed or relapse after first-line treatment (3, 4). Whereas, a substantial proportion of patients go on to receive intensive pharmacological care (5, 6).

Besides mental health outcomes, recent studies cast great concern on the physical health of depressed individuals. Depression is, in fact, accompanied by behavioral and biological features that are deleterious for physical health, particularly in the cardiovascular system (7). Moreover, when depression arises as a consequence of pre-existing physical problems, it may amplify disability, anticipate recurrences, and increase disease-related mortality (8, 9). Recently it was estimated that individuals with major depression die, on average, about 10 years earlier than those who are not depressed, even when excluding deaths by suicide (10–12).

There is wide agreement that current research and clinical efforts to address these issues are arguably not proportional to their gravity. There is an urgent need to develop and implement novel treatments that are effective to treat symptoms of depression and, at the same time, are beneficial for physical health (13). One such intervention is physical exercise, which is increasingly recognized as both an antidepressant agent (14) and a potent tool to delay mortality (15). The aim of this perspective article is to provide a concise update on the effectiveness of exercise for depression and cardiovascular mortality reduction. A specific section is dedicated to treatment of elderly patients, in consideration of their increasing demographic relevance (2). English-language reviews and meta-analyses published in the last 10 years were considered, identified with the following search string in the Pubmed database: (exercis<sup>∗</sup> [ti] OR "physical activity"[ti]) AND depress<sup>∗</sup> [ti] AND (review<sup>∗</sup> [pt] OR review<sup>∗</sup> [tiab]).

## DEPRESSION IS ASSOCIATED WITH A SHORTER LIFESPAN

Even if a direct causal role is still debated (16), depression could increase mortality through several mechanisms (10). First, it negatively impacts lifestyle choices. Individuals with depression tend to be sedentary (17, 18) and less physically fit than their non-depressed counterparts (19). Moreover, they exhibit higher rates of cigarette smoking (20–22), consume more alcohol (23), adopt low-quality dietary regimens (24), and become overweight (25, 26). Of note, some of these associations seem underlined by bi-directional causal links.

Second, depression is accompanied by dysregulation of several homeostatic systems (27). Depressed individuals commonly display dysregulation of the hypothalamic–pituitary– adrenocortical (HPA) axis (28–30), immune (31, 32), and autonomic nervous system (33), as well as metabolic imbalances (34).

Third, depression can raise mortality risk by increasing the incidence of physical illnesses or worsening the outcomes of existing ones. For instance, the presence of clinically significant depression has been found to increase the incidence and mortality of cardiovascular diseases (35, 36), as well as the mortality due to diabetes (37) and stroke (38). This phenomenon could stem, among other reasons, from placing additional stress on disorder-specific pathophysiologic mechanisms, but may also reflect poor adherence to medications or problematic health behaviors (39–41). In this regard, **Table 1** reports an overview of the relationship between depression, cardiovascular risk factors, and mortality.

## EXERCISE IS EFFECTIVE FOR THE PHYSICAL HEALTH OF DEPRESSED PATIENTS

Physical activity and exercise have a wide range of beneficial effects (72) that involve both "body" and "mind." Bearing in mind this is an artifactual and anachronistic convention, here we provide an overview of exercise effects on the body "from the neck down" that could be relevant to individuals with depression. **Table 1** reports recent literature addressing this issue.

Together with dietary caloric restriction, exercise is the main component of interventions that are effective at reducing and managing weight (73–75). The positive effect of exercise is likely mediated by enhanced regulation of appetite hormones (76) and by increased metabolic rate (47, 77, 78). Moreover, exercise improves sleep quality and duration (79).

Exercise also causes beneficial adaptations in homeostatic systems involved in the response to stress, including the HPA axis (80–82). Moreover, it dampens inflammatory processes while delaying the aging of the immune system (51–53). Exercise also improves the autonomic visceral control by restoring sympathovagal balance (57, 83, 84) Finally, it improves cardiorespiratory fitness both in healthy individuals (47) and individuals with depression (85).

While the formal acknowledgment of the salutary effects of exercise in the medical sciences has been a lengthy process, regular exercise is now recognized as an important lifestyle behavior that can ameliorate the negative impact of chronic diseases (86). Overall, it is estimated that exercise can reduce mortality to a similar extent as medications in individuals with coronary heart disease, stroke, heart failure, and diabetes (15). It would be urgent to verify if such findings can be translated to depressed subjects.

Among the many salutary effects of exercise, arguably the least researched—and probably the most controversial—are its effects on other lifestyle and health behaviors. Both the number of randomized controlled trials and the methodological quality of the trials in this area are rising. While concepts and methods continue to evolve, some early results related to smoking cessation and reducing problem drinking among individuals with mental health disorders show promise (87–89). However, at this stage, systematic reviews of the evidence on the effectiveness of exercise in promoting abstinence from smoking (60) or alcohol (58) indicate no beneficial effect. On the other hand, the effect of exercise on reducing the use of illegal substances is significant (90). In addition, whether a structured exercise intervention can reduce sedentary behavior or encourage engagement in subsequent physical activity remains hotly debated (64).

## EXERCISE IS EFFECTIVE AGAINST SYMPTOMS OF MAJOR DEPRESSION

Physical exercise has been shown to be an effective treatment for major depression in adults (14, 91) in several randomized controlled trials comparing it to a wide range of other treatments, including usual care, psychological interventions, and antidepressant medications (14, 92). Although there have been contrarian meta-analytic findings [e.g., (93)], closer inspection of methodological details reveals a pattern of debatable choices (91).

Exercise interventions consisting of three sessions per week for 12–24 weeks typically result in a medium to large reduction in the severity of depression, measured by symptom

TABLE 1 | Literature examining the relationship between depression, cardiovascular risk factors, cardiovascular mortality, and physical exercise in adults.

(Continued)

#### TABLE 1 | Continued

This table summarizes recent literature on: (a) the relationship between depression, cardiovascular risk factors and mortality due to cardiovascular diseases; (b) the effectiveness of exercise modifying such risk factors and mortality. The latest reviews for each topic were identified through multiple searches of the Pubmed database. Quantitative reviews or meta-reviews were preferred over qualitative or narrative ones. The number and type of primary studies is specified (cross-sectional vs. longitudinal; RCTs vs. controlled trials). Na, not available; RCTs, Randomized Controlled Trials; T2DM, Type 2 Diabetes Mellitus, CAD, Coronary Artery Disease; HF, Heart Failure; ACEi, Angiotensin Converting Enzyme Inhibitors; ARBs, Angiotensin II Receptor Blockers; OR, Odds Ratio; RR, Relative Risk; HR, Hazard Ratio; SMD, Standardized Mean Difference; CI, Confidence Intervals.

rating scales (91). Moreover, exercise interventions have been found to result in 22% higher likelihood of remission from depression than treatment as usual (93), the latter in turn being associated with the remission of about a third of patients (3, 4). Generally, exercise is well-tolerated and leads to about 18% of dropout rates (94). Based on the available data, the efficacy of exercise seems greater if it is aerobic, delivered in groups, and supervised by an instructor (95). Although there are relatively few head-to-head comparisons and duration of treatment may be different, the efficacy of exercise may be comparable in terms of magnitude to that of psychotherapies (3, 94–97) or antidepressant medications (98).

Some authors claim the psychological effects of exercise largely depend on "placebo," or "non-specific" psychosocial effects, such as attention by staff (99, 100). Consistently, exercise is still listed among "alternative and complementary" therapies in some guidelines [e.g., (101)]. Skepticism has been fueled, among other reasons, by difficulties to demonstrate a clear dose-response relationship, such as would be expected in drug trials. Recent studies, however, have started to detect significant associations between the intensity and length of exercise interventions, and their antidepressant efficacy (102, 103); of note, such relationship is likely to follow non-linear patterns (104). Another long-held belief among clinicians is that exercise does only ameliorate non-specific somatic symptoms, such as sleep and appetite changes. Whereas, extant results suggest that exercise indeed reduces core symptoms of depression, such as depressed mood, anhedonia, and suicidal ideation (105, 106). On the other hand, studies examining the effects of exercise interventions on cognitive function among individuals with depression [e.g., (107)] at present do not indicate substantial benefits (108–110).

Exercise may be effective improving several biomarkers that have been implicated in depression (e.g., impaired neuroplasticity, autonomic, and immune imbalances). However, at present, evidence derived from non-depressed individuals still needs to be replicated among clinical populations (111). Nevertheless, recent trials have begun to show efficacy in treating patients with severe mood disorders (112–114) and individuals with treatment-resistant depression, either alone or as an addon to medications (115, 116). Lastly, exercise can be effective for individuals who may present concerns about drug treatment, such as women with pregnancy or post-partum depression (117) and adolescents (118, 119).

At present, research is still needed to establish the efficacy of exercise in the long-term course of major depression. Some analyses suggest that the antidepressant effects may diminish beyond the duration of the exercise intervention (92). However, individuals who regularly engage in moderate physical activity maintain reduced risk of incurring depressive episodes (120, 121).

## EFFECTIVENESS OF EXERCISE IN LATE LIFE DEPRESSION

The clinical features and pathophysiology of late-life depression are largely distinct from that encountered among younger adults (122–124). Specifically, depression in late life is associated with a higher prevalence of physical illnesses, greater prevalence of cognitive impairments and inadequate response to antidepressant drugs (125–128). Despite these differences, late-life depression seems to respond to exercise as well as adult depression (129–131). Moreover, among studies appraised in recent meta-analyses, participants receiving exercise did not report any significant side effects. More recently, the SEEDS study showed that exercise was an effective add-on to antidepressant drugs for mild to moderate depression (132). Interestingly, adding exercise to antidepressant drugs primarily affected core symptoms of depression rather than somatic symptoms (133). Moreover, individuals receiving aerobic exercise plus antidepressants displayed greater improvements in cognition and autonomic balance compared to those only receiving antidepressants (134, 135). The intervention was well-received by patients and physicians alike (136).

Despite these promising results, the available evidence remains insufficient to conclude whether exercise can improve cognition in patients with late-life depression (108, 109). At present, studies suggest that exercise may not improve cognition among non-impaired, non-depressed individuals (137), but it may, to some extent, improve cognitive performance among individuals diagnosed with cognitive impairment (irrespective of depression), dementia, or physical diseases (138–141).

## HOW SHOULD EXERCISE BE PRESCRIBED TO INDIVIDUALS WITH DEPRESSION?

Depression is usually treated by primary care physicians, psychiatrists, and psychologists. Exercise interventions can be delivered by professionals with a variety of disciplinary backgrounds, including group exercise leaders, personal trainers, clinical exercise physiologists, wellness specialists, and physical therapists. Given the challenging cognitive and affective features of depression, it is recommended that exercise for individuals with depression should be delivered by professionals with specific experience in mental health care (142). In other words, a well-integrated, collaborative approach is essential.

A collaborative approach begins with physicians willing to introduce the idea of exercise as a possible treatment options to individuals expressing depression complaints. However, proposals to introduce exercise to the armamentarium of interventions for the treatment of depression are often met with skepticism by physicians due to various perceived barriers (143, 144). These barriers may stem, at least in part, from high-profile reviews and treatment recommendations that downplay the relevant evidence. A recent review, for example, characterized any benefits of exercise, even against non-active control interventions, as merely "modest," alleged that "highquality clinical studies investigating the effect of exercise for treating depression among older patients are lacking," and raised doubt about whether older individuals with depression would be "willing to participate actively in an exercise program" (145). A counterpoint is that, to a large extent, such statements reflect a limited or outdated assessment of the evidence (146, 147). While the evidence base continues to evolve, there are already several randomized controlled trials with positive results that satisfy the standard criteria for high methodological quality (91). Furthermore, provided that proper therapeutic alliances are established within a stepped-care collaborative framework (136), many individuals with subthreshold, mild, and moderate depressive symptoms will opt for exercise and will demonstrate satisfactory adherence.

Several groups have published recommendations for developing exercise prescriptions for individuals with depression, based on both empirical evidence and clinical experience (148– 152). While we endorse these recommendations, we should note that the optimal exercise prescription for the treatment of depression remains unknown, insofar as the relation between the "dose" of exercise (i.e., intensity, frequency, session duration) and the therapeutic response remains understudied. Therefore, any prescription recommendations at the present stage are essentially derived from general exercise prescription guidelines, which were developed primarily for the improvement and maintenance of physical fitness and cardiometabolic health (153). Therefore, we wish to highlight an emerging trend in exercise prescription, which may be especially relevant to the treatment of depression, namely affect-based exercise prescription (154). This method expands the traditional focus of exercise prescriptions from the dual goal of maximizing fitness gains while minimizing risk to a model that also aims to ensure that participants consistently derive pleasant affective experiences. The inclusion of pleasure as a central consideration is intended to enhance what is often the Achilles' heel of lifestyle or behavior-change interventions, namely adherence. In a typical affect-based prescription, the exercise participant is shown a simple rating scale (e.g., one ranging from +5: "I feel very good" to −5: "I feel very bad") and is instructed to self-regulate his or her exercise intensity and duration to maintain a rating of +3 or higher.

Individuals with depression can experience exercise as pleasant and affect-enhancing (155–157). Among non-depressed adults, affective responses to a bout of exercise have been found in correlational studies to be associated with the amount of physical activity individuals choose to do (158), while experimental manipulations resulting in improved affective responses have been shown to increase the amount of physical activity performed over a subsequent period of 6 months (159). Early evidence among individuals with depression indicates that affective responses to a bout of exercise may predict treatment response (160, 161). While randomized controlled trials investigating the efficacy, effectiveness, and cost-effectiveness of affect-based exercise prescriptions for the treatment of depression are not yet available, this method seems to hold promise for clinical application due to its simplicity, making it appealing to physicians who lack specialized training in exercise and to healthcare organizations concerned about implementation costs.

## CONCLUSIONS

The premature mortality of individuals with depression is an alarming public health concern, which is exacerbated by the present inability to offer satisfactory treatments. Physical exercise represents an underutilized intervention that may uniquely address both concerns at the same time. First, exercise offers numerous physical benefits, which can counteract several mechanisms postulated to increase mortality risk in depression. Second, if prescribed and delivered correctly, exercise can be as effective as other first-line treatments, while being mostly free of adverse side-effects.

While there is a need of pragmatic trials to evaluate the long-term effects of exercise and its cost-effectiveness, clinicians in the mental health sector should acknowledge this ancient, yet new treatment option and should start to use it to the benefit of patients.

## REFERENCES

## AUTHOR CONTRIBUTIONS

MB and PE conceived and drafted the work. MM, DZ, SC, PC, LC, GS, SZ, and MA contributed to revising it critically and approving the content.

## FUNDING

The study has been funded by a grant of the Italian Ministry of Education, Universities and Research within the framework of the Progetti di Rilevante Interesse Nazionale (PRIN) — year 2015.

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randomized controlled trials. J Am Heart Assoc. (2015) 4:e002014. doi: 10.1161/JAHA.115.002014

meta-analysis. J Am Acad Child Adolesc Psychiatry (2016) 55:580–90. doi: 10.1016/j.jaac.2016.04.016

of randomized controlled trials. Clin Interv Aging (2017) 12:773–83. doi: 10.2147/CIA.S135700

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Belvederi Murri, Ekkekakis, Magagnoli, Zampogna, Cattedra, Capobianco, Serafini, Calcagno, Zanetidou and Amore. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Metabolic Syndrome in Psychotic Disorder Patients Treated With Oral and Long-Acting Injected Antipsychotics

Antonio Ventriglio<sup>1</sup> \*, Ross J. Baldessarini 2,3, Giovanna Vitrani <sup>1</sup> , Iris Bonfitto<sup>1</sup> , Angela Chiara Cecere<sup>1</sup> , Angelo Rinaldi <sup>1</sup> , Annamaria Petito<sup>1</sup> and Antonello Bellomo<sup>1</sup>

<sup>1</sup> Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy, <sup>2</sup> International Consortium for Psychotic & Mood Disorder Research, McLean Hospital, Belmont, MA, United States, <sup>3</sup> Department of Psychiatry, Harvard Medical School, McLean Hospital, Boston, MA, United States

#### Edited by:

Andrea Fiorillo, Università degli Studi della Campania "Luigi Vanvitelli" Naples, Italy

### Reviewed by:

Francesco Bartoli, Università degli studi di Milano Bicocca, Italy Steve Simpson Jr, The University of Melbourne, Australia Beth McGinty, Johns Hopkins University, United States

> \*Correspondence: Antonio Ventriglio<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Psychosomatic Medicine, a section of the journal Frontiers in Psychiatry

Received: 22 August 2018 Accepted: 17 December 2018 Published: 16 January 2019

#### Citation:

Ventriglio A, Baldessarini RJ, Vitrani G, Bonfitto I, Cecere AC, Rinaldi A, Petito A and Bellomo A (2019) Metabolic Syndrome in Psychotic Disorder Patients Treated With Oral and Long-Acting Injected Antipsychotics. Front. Psychiatry 9:744. doi: 10.3389/fpsyt.2018.00744 Background: Severe mental illnesses are associated with increased risks for metabolic syndrome (MetS) and other medical disorders, often with unfavorable outcomes. MetS may be more likely with schizoaffective disorder (SzAff) than schizophrenia (Sz). MetS is associated with long-term antipsychotic drug treatment, but relative risk with orally administered vs. long-acting injected (LAI) antipsychotics is uncertain.

Methods: Subjects (n = 151 with a DSM-IV-TR chronic psychotic disorder: 89 Sz, 62 SzAff), treated with oral or LAI antipsychotics were compared for risk of MetS, initially with bivariate comparisons and then by multivariate regression modeling.

Results: Aside from measures on which diagnosis of MetS is based, factors preliminarily associated with MetS included antipsychotic drug dose, "high-risk" antipsychotics associated with weight-gain, older age and female sex. Defining factors associated with diagnosis of MetS ranked in multivariate regression as: higher fasting glucose, lower LDL cholesterol, higher diastolic blood pressure, and higher BMI. Risk of MetS with antipsychotics ranked: quetiapine ≥ clozapine ≥ paliperidone ≥ olanzapine ≥ risperidone ≥ haloperidol ≥ aripiprazole. Other associated risk factors in multivariate modeling ranked: higher antipsychotic dose, older age, and SzAff diagnosis, but not oral vs. LAI antipsychotics

Conclusions: SzAff diagnosis and higher antipsychotic doses were associated with MetS, whereas orally vs. injected antipsychotics did not differ in risk of MetS.

Keywords: metabolic syndrome, antipsychotics, long-acting injected, schizoaffective, schizophrenia

## INTRODUCTION

Persons with severe mental illnesses have increased risk for metabolic disorders, including metabolic syndrome (MetS), characterized by obesity, type 2 diabetes mellitus, dyslipidemia, and hypertension (1). Such disorders appear to be related to an unhealthy diet, lack of regular exercise, adverse effects of psychotropic drugs, and possibly to undefined risk factors associated with the illnesses themselves (2, 3). Much of the research on this topic has involved patients diagnosed with chronic psychotic or mood disorders, particularly schizophrenia (Sz) and bipolar disorder

**139**

(2, 4–6). Few studies have compared physical health of subjects diagnosed with schizoaffective disorder (SzAff) to that of other patients with other psychotic-disorder diagnoses, including Sz, but SzAff patients may have a greater risk of MetS than those with other major psychiatric disorders (6). SzAff patients are characterized by emotional and behavioral instability over time as well as psychotic features, and often are treated with relatively complex pharmacological regimens (7). Both emotional instability and complex treatments may contribute to an increased risk of metabolic disorders (1).

Also uncertain is whether specific types of medicines differ appreciably in their associations with risks of metabolic disorders. In particular, the extent to which relative metabolic risks of modern or second-generation antipsychotics (SGAs) and their long-acting injected (LAI) preparations differ from older or orally administered antipsychotics remains uncertain (1, 8–10).

The preceding considerations led us to compare clinical measures, in particular indices of metabolic health, among SzAff vs. Sz patient-subjects to identify factors associated specifically with MetS, including comparison of orally administered vs. LAI antipsychotics. We hypothesized that SzAff subjects would have a higher risk of MetS than Sz subjects, and that the risk might be lower with LAI antipsychotic treatments.

## METHODS

From June 2014 to February 2017, we enrolled study subjects as part of a program monitoring the health of psychotic disorder patients attending the Day Hospital Service for Severe Mental Disorders in the Psychiatric Department at the University of Foggia Medical Center. A total of 151 consecutive patients were enrolled as study-subjects, including 89 diagnosed with Sz and 62 as SzAff by two expert clinicians (AB, AV) based on DSM-IV-TR (Diagnostic and Statistical Manual of mental disorders-Text Revision) criteria (11). Treatments were selected clinically and included oral antipsychotics (n = 64, with or without mood-stabilizers or antidepressants) as well as LAI antipsychotics (n = 87, usually as monotherapy).

All subjects provided written informed consent to participate, after study procedures approved by the University of Foggia medical center ethics committee were explained to them. Patients were enrolled in a stable phase of their illness and treatments; candidates who required psychiatric hospitalization, had revised treatment protocols within the previous 6 months, were actively abusing alcohol or drugs (confirmed by urine assays), or were pregnant, were excluded from the study.

Current psychiatric morbidity was assessed and rated with the Positive and Negative Syndrome Scale (PANSS) (12), and Brief Psychiatric Rating Scale (BPRS) (13) by two experienced psychiatrist-investigators (AB, AV). Raters were held unaware of treatments given, and their ratings yielded high, independent, interrater agreement (χ <sup>2</sup> ≥ 0.90). Being considered "mildly ill" corresponded to a PANSS total score of ≤58 or BPRS score of ≤31, "moderately ill" corresponded to PANSS ratings of 59–75 or BPRS scores of 32–40, "moderately severely ill" corresponded to PANSS of 76–95 or BPRS of 41–53, and "severely ill" corresponded to a PANSS of 96–116 or BPRS of 54–126 (12, 13).

We also collected data on: demographics (sex, age, employment status), current pharmacological treatments (oral or LAI antipsychotics, mood stabilizers [MSs], and antidepressants [ADs]), and their doses; anthropometric and metabolic measures (height [cm] and weight [kg] for body-mass index [BMI]), systolic and diastolic blood pressure (mm Hg), pulse (beats/min); serum concentrations of fasting glucose (FBS; mg/dL), %-glycated hemoglobin (Hgb-A1c), total cholesterol (mg/dL), low density lipoproteins (LDL; mg/dL), high density lipoproteins (HDL; mg/dL), triglycerides (mg/dL); waist circumference (cm), electrocardiographic rate-corrected QT repolarization interval (QTc, msec); serum levels of prolactin (ng/dL), thyroid stimulating hormone (TSH, mIU/L), and free thyroxin and triiodothyronine. We also recorded adverse events associated with treatment, and rated treatment-adherence with the 30-item Drug Attitude Inventory (DAI-30) (14).

We rated subjects for the presence of MetS defined by current, revised International Diabetes Federation (IDF) criteria, American Heart Association and International Association for the Study of Obesity (15, 16). MetS required meeting ≥3 of the following 5 criteria: [a] large waist circumference (≥102 cm in men, ≥88 cm in women); [b] elevated serum triglycerides (≥150 ng/dL); [c] low HDL-cholesterol (<40 mg/dL in men and <50 in women); high blood pressure (≥130 mm Hg systolic or ≥85 mm diastolic); elevated glucose as fasting blood sugar (FBS >100 mg/dL).

To facilitate comparisons, we converted antipsychotic doses to approximate oral daily mg-chlorpromazine-equivalents (CPZeq); LAI antipsychotic doses were estimated as total mg doses per days of injection cycles for conversion to CPZ-eq (17, 18). For MSs, we converted dosages to approximate daily mg-equivalents of lithium carbonate (Li-eq) (18, 19). Antidepressants were noted as being prescribed or not.

We compared measures collected among subjects diagnosed with SzAff and Sz, treated with LAI and oral antipsychotics, emphasizing comparisons of subjects with vs. without MetS. Data analyses used commercial statistical programs (Statview-5, SAS Corp., Cary, North Carolina, USA for spreadsheets; Stata.13.0, Stata Corp., College Station, Texas, USA). Data are presented as means ± standard deviation (SD) or with 95% confidence intervals (CI), or as percentages (%), unless stated otherwise. Continuous data were compared using nonparametric Mann-Whitney rank-sum test (z-score) to avoid problems of non-normal distribution of values, and categorical data were tested with contingency tables (χ 2 ). Factors yielding p < 0.10 in preliminary bivariate comparisons were considered in multivariate logistic regression modeling, with presence of MetS as the outcome measure.

## RESULTS

## Sample Characteristics and Treatments

The 151 patient-subjects were aged 42.1 ± 12.4 years; 52.9% were men, 18.5% were employed. Diagnoses included Sz (n = 89; 58.9%) and SzAff (n = 62; 41.1%). More men than women were diagnosed with Sz (χ <sup>2</sup> = 6.76; p = 0.009). Treatments included oral antipsychotics in 42.3%, and LAI antipsychotics in 57.7% (none received both). Antipsychotics were combined with moodstabilizers (MSs) in only 14.5%, or with antidepressants (ADs) in 12.3% (ranking by use: duloxetine > paroxetine > citalopram or S-citalopram > sertraline). Both adjunctive treatments were given selectively with oral antipsychotics, by 6.4- (MSs) or 7.0 times more (ADs; both p ≤ 0.006) among SzAff than Sz subjects. Antipsychotic doses averaged 313 ± 329 mg/day CPZ-eq, and MS (carbamazepine, lithium carbonate, sodium valproate) total daily Li-eq doses averaged 650 ± 244 mg. Overall, clinical ratings averaged 75.0 ± 34.7 for PANSS and 51.6 ± 23.6 for BPRS; both indicate moderate symptomatic severity, even though all patients reported clinical and treatment stability for at least six continuous preceding months. Prolonged, stable dosing assured that even the LAI antipsychotics were at pharmacokinetic steady-state.

Subjects who received LAI vs. oral antipsychotics had significantly lower levels of symptomatic morbidity. PANSS scores were, respectively, 58.0 ± 27.6 vs. 98.1 ± 29.9, and BPRS scores averaged 40.1 ± 15.0 vs. 67.1 ± 24.5 (z-scores = 7.76 and 6.85, both p < 0.0001).

No subject was considered to have a substance-use disorder, as was supported by urine drug assays, consistent with current substance abuse as an exclusion criterion. Adherence to prescribed treatments was considered good, as supported by a DAI-30 score of 9.64 ± 2.19 (of a total maximum of 30). There was a moderate rate of reported, treatment-associated, adverse events (19.8%), most of which involved motor slowing or mild tremor.

## Risk and Measures Associated With Metabolic Syndrome

Of the entire sample, 31.8% met diagnostic criteria for MetS (**Table 1**): 42.3% of women and 22.5% of men. Overall, BMI averaged 27.7 ± 5.72 kg/m<sup>2</sup> , in the nearly obese range. However, 35.8% of subjects (38.0% of women and 33.8% of men) had BMI of ≥28.8 kg/m<sup>2</sup> , taken to indicate obesity (15, 16).

Other factors possibly associated with MetS included: female sex, older age, SzAff vs. Sz diagnosis, higher BPRS psychosis score (which was associated with greater APD doses: Spearman r<sup>s</sup> = 0.252, slope = 1.68 [0.653–2.72], p = 0.002), treatment with antipsychotics with relatively high risk of obesity and MetS (clozapine, olanzapine, paliperidone, quetiapine; **Table 2**), higher CPZ-eq antipsychotic dose, but not orally administered vs. LAI antipsychotics (**Table 1**). Additional metabolic and cardiovascular measures did not differ between subjects with vs. without MetS, including assays of TSH and thyroid hormones, prolactin, pulse rate, and ECG repolarization interval (QTc), nor did BPRS or PANSS ratings of psychosis-severity differ (**Table 1**).

As expected, measures that contributed to its diagnosis were highly deviant among subjects with MetS, including obesity, waist circumference, blood pressure, FBS, hemoglobin glycation, serum concentrations of cholesterol (higher total and LDL, lower HDL) and triglycerides (**Table 1**). BMI was not used to define MetS but was markedly elevated in subjects with MetS (**Table 1**). We also tested the strengths of association of such measures with the diagnosis of MetS using logistic regression modeling (**Table 2**).

## Treatments and Metabolic Syndrome

LAI antipsychotics were more prescribed than oral agents (57.7% vs. 42.3%), particularly among Sz vs. SzAff subjects (65.5% vs. 34.5%; χ <sup>2</sup> = 3.67, p = 0.055), whereas oral agents were used in half of both diagnostic groups. Average CPZ-eq daily doses of oral and LAI antipsychotics among Sz (295 mg) and SzAff subjects (338 mg) did not differ significantly. LAI paliperidone palmitate was the most prescribed antipsychotic agent in both diagnostic groups (Sz 34.8%; SzAff 27.4%; 31.8% overall); other LAI antipsychotic usage ranked: risperidone extended release (10.6%) > aripiprazole long acting (9.28%) > olanzapine palmitate (4.64%). Usage of oral antipsychotics ranked: risperidone (Sz 11.2%, SzAff 12.9%, 11.9% overall) > haloperidol (7.28% overall) = olanzapine (7.28%) > aripiprazole (5.30%) > quetiapine (3.98%) ≥ paliperidone (3.31%) = clozapine (3.31%) > ziprasidone 1.32%.

Several metabolic measures were somewhat more favorable with use of LAI vs. oral antipsychotics, including total cholesterol (192 vs. 223 mg/dL), LDL cholesterol (125 vs. 175 mg/dL), triglycerides (148 vs. 188 mg/dL); waist circumference (103 cm [40.6 in] vs. 117 cm [46.1 in]); the cardiac QTc repolarization interval (399 vs. 413 msec); and circulating prolactin (42.7 vs. 61.3 ng/dL).

We compared the prevalence of MetS among subjects treated with different antipsychotic agents. Relatively high-risk drugs were quetiapine (83.3%), clozapine (60.0%), paliperidone (34.0%) and olanzapine (33.4%; **Table 3**). Of note, these risks were not accounted for by dose as prevalence of MetS and CPZ-eq doses were not significantly correlated (**Table 3**).

## Multivariable Modeling: Factors Associated With Metabolic Syndrome

We used multivariable logistic regression modeling to identify factors associated independently with MetS. In order of significance, associated factors ranked: CPZ-eq antipsychotic dose, older age, and SzAff > Sz diagnosis, but not oral vs. LAI antipsychotics (**Table 4**).

## DISCUSSION

This study involved 151 patient-subjects with chronic psychotic disorders who had been clinically stable on constant medication regimens for at least 6 months. LAI antipsychotics were given to 57.7%, and oral agents to 42.3%. LAI agents were more often given to Sz subjects, whereas use of oral antipsychotics was similarly prevalent in both SzAff and Sz subjects. SzAff subjects were also 6–7-times more likely to be given co-treatment with a mood-stabilizer or antidepressant. All subjects were rated at moderate symptomatic severity by PANSS and BPRS. Adherence to prescribed treatments was rated as good by DAI-30 score, and the risk of adverse effects was moderate at 19.8%.

#### TABLE 1 | Factors associated with metabolic syndrome in 151 psychotic disorder patients.

BPRS, Brief Psychiatric Rating Scale; PANSS, Positive and Negative Syndrome Scale; LAI, long-acting injectable antipsychotics; CPZ, chlorpromazine; DAI, Drug Attitude Inventory; BMI, body-mass index; BP, blood pressure; ECG, electrocardiogram; Hgb, hemoglobin; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TSH, thyroid-stimulating hormone. <sup>a</sup>Mann-Whitney (z-score) or contingency table (χ 2 ). <sup>b</sup>Clozapine, olanzapine, paliperidone, quetiapine.

The overall prevalence of MetS (31.8%) was moderate, but ranged from 18.2% with aripiprazole to 83.3% with quetiapine (**Table 3**). By comparison, reported prevalence of MetS in patients with psychotic disorders has ranged from 30 to 67% (1, 7, 20, 21). Based on multivariate modeling, factors associated with MetS were antipsychotic dose, older age, and SzAff diagnosis, but not oral vs. LAI antipsychotics.

Of note, the present finding of significantly greater risk of MetS with SzAff vs, Sz diagnoses supports one hypothesis of this study, and adds to a previous suggestion of such a relationship (6). Although use of complex medication regimens was much more prevalent among SzAff subjects, these were infrequent and not significantly associated with risk of MetS. In addition, CPZ-eq antipsychotic doses were somewhat higher among SzAff subjects, although both factors appeared to operate somewhat independently (**Table 4**). Nevertheless, we suggest that the relative instability of SzAff disorders contributes to the use of more complex treatments (7) and this feature as well perhaps as intrinsic characteristics of such patients may contribute to risk of MetS.

In addition, contrary to prediction, we did not find a significant difference in risk of MetS in association with treatment with oral vs. LAI antipsychotics. This finding appears to be consistent with other recent reports indicating that LAI agents may not be safer than oral antipsychotics (8, 10). However, several measures tended to be less abnormal with LAI treatments (including lower total and LDL cholesterol, triglycerides and prolactin, smaller waist-circumference, and

Model fit χ <sup>2</sup> = 93,5, p < 0.0001. Not associated, age, LDL level, waist-circumference.

TABLE 3 | Risk of metabolic syndrome: antipsychotic agents and doses.

Risk of MetS is not significantly associated with CPZ-eq dose (Spearman r<sup>s</sup> = 0.402, p = 0.325), but the drugs differ overall (χ <sup>2</sup> = 13.4, p = 0.04). Relatively high-risk drugs are quetiapine, clozapine, paliperidone and olanzapine.

TABLE 4 | Multivariable logistic regression modeling: risk factors associated with metabolic syndrome.

Model fit χ <sup>2</sup> = 17.9, p = 0.001. Not associated, sex, diagnosis, psychosis severity. (BPRS rating).

shorter QTc interval). In addition, we found marked differences in risk of MetS between particular antipsychotic agents, with higher risk associated with quetiapine, clozapine, paliperidone,

## REFERENCES

and olanzapine, which are known to be associated with relatively high risks of weight-gain (1, 2, 18, 22, 23).

### Limitations

The study included a relatively small number of subjects and its findings may not generalize to other sites. Its cross-sectional design supports associations with MetS, but precludes causal inferences. In addition, estimates of CPZ-eq doses of LAI antipsychotics are not adjusted for probable but uncertain differences in bioavailability of injected vs. orally administered drugs.

## CONCLUSIONS

This observational study of 151 patient-subjects with chronic psychotic disorders found a moderate prevalence of MetS (31.8%), which was associated with being overweight or obese and with antipsychotic agents prone to leading to weight-gain, as well as higher antipsychotic CPZ-eq doses, and older age. Notably, risk of MetS was somewhat greater among SzAff than Sz subjects, but did not differ significantly between treatment with oral and LAI antipsychotics nor with the relatively infrequent use of adjunctive mood-stabilizers or antidepressants. However, several metabolic measures tended to be less abnormal among SzAff than Sz subjects. The association of MetS with SzAff (more than with Sz) probably reflects the complexity of SzAff disorders and their pharmacological treatment, including somewhat higher antipsychotic doses and more co-treatment with mood-stabilizers and antidepressants, but may also reflect other unknown characteristics of the disorders themselves.

## AUTHOR CONTRIBUTIONS

AV, GV, IB, AC, AR, and AP recruited patients and collected data. AV and RB wrote the paper. AB supervised clinical work and the manuscript drafting.

## FUNDING

Supported by Department of Clinical and Experimental Medicine of University of Foggia. Supported, in part, by a grant from the Bruce J. Anderson Foundation and by the McLean Private Donors Psychopharmacology Research Fund (to RB).

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Ventriglio, Baldessarini, Vitrani, Bonfitto, Cecere, Rinaldi, Petito and Bellomo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

## Need for Cardiovascular Risk Reduction in Persons With Serious Mental Illness: Design of a Comprehensive Intervention

Arlene T. Dalcin<sup>1</sup> , Gerald J. Jerome<sup>2</sup> , Lawrence J. Appel <sup>1</sup> , Faith B. Dickerson<sup>3</sup> , Nae-Yuh Wang<sup>1</sup> , Edgar R. Miller <sup>1</sup> , Deborah R. Young<sup>1</sup> , Jeanne B. Charleston<sup>1</sup> , Joseph V. Gennusa<sup>1</sup> , Stacy Goldsholl <sup>1</sup> , Ann Heller <sup>1</sup> , A. Eden Evins <sup>4</sup> , Corinne Cather <sup>4</sup> , Emma E. McGinty <sup>5</sup> , Rosa M. Crum<sup>6</sup> and Gail L. Daumit <sup>1</sup> \*

<sup>1</sup> Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States, <sup>2</sup> Department of Kinesiology, Towson University, Baltimore, MD, United States, <sup>3</sup> Sheppard Pratt Health System, Baltimore, MD, United States, <sup>4</sup> Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States, <sup>5</sup> Department of Health Policy and Management, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States, <sup>6</sup> Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States

#### Edited by:

Andrea Fiorillo, Università Degli Studi Della Campania Luigi Vanvitelli Naples, Italy

#### Reviewed by:

Luca Steardo, Università Degli Studi Della Campania Luigi Vanvitelli Caserta, Italy Carmen Moret-Tatay, Catholic University of Valencia San Vicente Mártir, Spain

> \*Correspondence: Gail L. Daumit<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Psychosomatic Medicine, a section of the journal Frontiers in Psychiatry

Received: 15 September 2018 Accepted: 31 December 2018 Published: 08 February 2019

#### Citation:

Dalcin AT, Jerome GJ, Appel LJ, Dickerson FB, Wang N-Y, Miller ER, Young DR, Charleston JB, Gennusa JV, Goldsholl S, Heller A, Evins AE, Cather C, McGinty EE, Crum RM and Daumit GL (2019) Need for Cardiovascular Risk Reduction in Persons With Serious Mental Illness: Design of a Comprehensive Intervention. Front. Psychiatry 9:786. doi: 10.3389/fpsyt.2018.00786 Persons with serious mental illness (SMI) comprise a high-risk group for cardiovascular disease (CVD)-related mortality with rates at least twice those of the overall US. Potentially modifiable CVD risk behaviors (tobacco smoking, obesity, physical inactivity, unhealthy diet) and risk factors (hypertension, diabetes, dyslipidemia) are all markedly elevated in persons with SMI. Evaluations of programs implementing integrated medical care into specialty mental health settings have not shown meaningful effects on CVD risk factor reduction. Rigorously tested, innovative interventions are needed to address the large burden of CVD risk in populations with SMI. In this article, we describe the design of a comprehensive 18-month intervention to decrease CVD risk that we are studying in a randomized clinical trial in a community mental health organization with psychiatric rehabilitation programs. The individual-level intervention incorporated health behavior coaching and care coordination/care management to address all seven CVD risk behaviors and risk factors, and is delivered by a health coach and nurse. If successful, the intervention could be adopted within current integrated care models and significantly improve the physical health of persons with SMI.

Keywords: serious mental disorder, cardiovascular risk, intervention, care coordination, behavioral coaching

## INTRODUCTION

Persons with serious mental illness (SMI) comprise a high-risk group for cardiovascular disease (CVD)-related mortality with rates at least twice those of the overall US (1–5). Potentially modifiable CVD risk behaviors (tobacco smoking, obesity, physical inactivity, unhealthy diet) and risk factors (hypertension, diabetes, dyslipidemia) are all markedly elevated in persons with SMI (6–10). The American Heart Association set strategic goals to improve cardiovascular (CV) health to ideal levels for each risk factor and reduce CVD mortality by 20% for all Americans by 2020 (11). However, persons with SMI often have challenges in everyday functioning due to cognitive impairment and ongoing psychiatric symptoms (12, 13). Together with high prevalence of substance use, unemployment, low-income and social isolation, these factors make implementing effective CVD risk reduction interventions challenging for this population (13–17). Adapted behavioral weight loss interventions and smoking cessation interventions tailored to persons with SMI have shown to be efficacious in clinical trials (18–21), however, evidenced-based interventions are needed that address more than one CVD risk factor. Without special efforts to develop interventions that promote CV health and control risk factors in persons with SMI, health disparities will persist and likely worsen.

While in the general population there is substantial evidence that non-physician interventionists (e.g., care managers) who facilitate and coordinate treatment with primary care physicians (PCPs) can improve multiple CVD risk factors (22–28), evidence for effective interventions in populations with SMI is needed. To address the premature mortality from CVD and other medical causes (3, 29–32) and need for improved access to quality care for physical health conditions (33, 34) among people with SMI, there has been a recent increase in implementation of programs integrating medical care into mental health settings (35–45).

In the US, one such model is the behavioral health home (BHH), which incorporates primary care coordination and management into the specialty mental healthcare setting (35–42). However, results from evaluations of BHHs and other integrated programs to-date have been mixed with either no or minimal effects on actual CVD risk factors (37, 46–51).

Thus, rigorously tested, innovative interventions are needed to address the large burden of CVD risk in populations with SMI. Here we describe the design and implementation of a comprehensive risk reduction intervention incorporating health behavior coaching and care coordination/care management to address all CVD risk factors in persons with SMI that we are studying in a randomized clinical trial.

## TRIAL STUDY DESIGN

This community organization-based two-arm randomized clinical trial (the IDEAL trial) tests an 18-month comprehensive, practical risk reduction program compared to control in reducing CVD risk as assessed by the global Framingham Risk score (52) in persons with SMI. Participants were randomized to receive a control condition or the active intervention, which incorporates health behavior coaching and care coordination/care management to improve CVD risk behaviors and factors. Individual CVD risk behaviors and factors comprise secondary outcomes.

## PARTICIPANTS AND SETTINGS

Two hundred sixty-nine participants with SMI 18 and older and at least one CVD risk factor (hypertension, diabetes mellitus, dyslipidemia, current tobacco smoker, or BMI ≥ 25 kg/m<sup>2</sup> ) were enrolled in the study. Exclusion criteria included having a CVD event in the prior 6 months, a serious medical condition limiting life expectancy, or an active alcohol or substance use disorder, pregnancy, planning on leaving the community in 6 months or the geographic area in 18 months. Serious mental illness diagnosis was assessed by chart review. The study was conducted in partnership with a large community mental health organization that provides outpatient services including psychiatric rehabilitation programs (PRPs). PRPs serve persons with SMI offering vocational and skills training, coordination of behavioral health and social services, and normally provide breakfast and lunch to attendees. We implemented the study at four organization sites with PRPs. As part of our partnership with the community mental health organization and to encourage environments conducive to healthy behaviors, we provided training and resources to promote group physical activity classes open to all program attendees, and a dietician to consult with PRP kitchen staff to provide healthier meals.

## INTERVENTION OVERVIEW

We adopted the American Heart Association (AHA) Life's Simple 7 goals and modified some (e.g., 10 lb. weight loss instead of BMI < 25) to provide intermediate targets achievable over the 18-month intervention (11). (**Table 1**) To work toward these goals, participants in the active intervention met individually with a health coach and a nurse who provided: (1) tailored CVD risk reduction education and counseling; (2) collaboration with physicians to advocate for appropriate management of CVD health risks; and (3) coordination with mental health staff and social supports to encourage and motivate participants to reach individually tailored CV health goals.

## THEORETICAL APPROACH

Behavioral aspects of the IDEAL intervention incorporate social cognitive theory and behavioral self-management concepts (54, 55). Motivational interviewing, is well suited for adults with SMI in that it is patient-centered, and uses a guiding style to enhance intrinsic motivation to improve CVD risk-related behaviors and promote medication adherence (56–59). The intervention also used solution-focused therapy, a positive-oriented, goaldirected technique emphasizing solutions rather than problems (60, 61). These approaches are useful in helping individuals gain confidence from small successes while staying focused on positive long-term changes.

The intervention fits well within a psychiatric rehabilitation framework because rehabilitation models emphasize skill building and goal setting and incorporate reinforcements as part of a behavioral change strategy (62–65). Evidence demonstrates the success of points/reward systems for persons with SMI in improving social interactions, work-related task performance, and other adaptive behaviors (66–74). The IDEAL intervention uses a point system to reward recommended behaviors (e.g., low carbon monoxide (CO) values consistent with no recent smoking, attending group exercise classes). Points can be traded for inexpensive items (e.g., pen, key chain) or saved for larger rewards (e.g., CD player).

The intervention is tailored to meet the cognitive needs of adults with SMI, characterized by memory and executive function deficits (75, 76). Participant materials have high readability and simplicity of messages, and streamlined paper tracking logs correspond to the intervention's lifestyle change

\*Based on AHA Strategic Goals and prevailing national guidelines modified for the trial, and tailored to participant needs. \*\*CVD risk-based target also used (53).

approach. In addition, in-person sessions include techniques such as emphasizing learning through repetition, modeling and demonstrating a few specific skills repeatedly; breaking material into small units; and rehearsing behavioral skills (12, 77, 78).

The intervention utilizes concepts drawn from the overlapping constructs of care management and care coordination. Care management is a patient-centered, teambased approach to increase delivery of evidenced-based care for chronic medical conditions (79). Care coordination emphasizes the deliberate organization of patient activities and the sharing of relevant information among all concerned parties to achieve better patient care (80). The IDEAL intervention team includes a nurse and a health coach, who work together to facilitate communication and coordination between participants, providers, and mental health program staff for all aspects of CVD risk factor management.

## INTERVENTION STAFF

The health coach is a facilitator with training in health behavior change and individual-level counseling with a skill level typical for a community health educator. When possible, the coach is an employee of the mental health organization; the position is modeled after one that would be feasible and sustainable in a community mental health setting. The coach, embedded in the PRP, is well-positioned to work with (other) community mental health program staff and take advantage of everyday interactions with staff and participants to encourage and support health behavior change and facilitate coordination of care for CVD risk factors. The registered nurse is an intervention team member who serves as a clinical resource addressing all aspects of CVD risk factor status. The coach and nurse report to an intervention director with motivational interviewing and health behavior change expertise. The intervention director implements quality assurance (**Table 2**), and may also provide direct services to participants.

## INTERVENTION APPROACH

The core elements of the intervention include health behavior coaching, coordination of care and care management.

## Health Behavior Coaching

Participants received 20–30 min individual coaching sessions, with weekly sessions for the first six months and at least biweekly thereafter, based on participant need. Guided by the participant's abilities and interests, the health coach addressed CVD risk and TABLE 2 | Quality assurance techniques used in comprehensive cardiovascular risk reduction intervention for adults with serious mental illness.

targeted behaviors either simultaneously or sequentially. The sessions used motivational interviewing strategies with an initial focus on building rapport and establishing a working alliance. Sessions included a review of the participant's risk behaviors to identify knowledge deficits and to set short-term behavioral goals. The coach used solution-focused therapy to support attainment of individual goals. Participants were encouraged to self-monitor with simple tracking tools as appropriate for their cognitive abilities. The coach reviewed tracking data with participants to reinforce progress, identified triggers and highrisk situations, and formulated new behavioral plans. The nurse provided educational and counseling sessions related to specific CVD risk factors (e.g., diabetes). The intervention sessions may include family members or peers to support the participant for better control of risk factors (e.g. tobacco smoking).

## Care Management and Care Coordination

The nurse mets with participants for medication-related counseling to address issues with adherence and plan for physician appointments, prioritizing those with uncontrolled risk factors. He/she shared information on participant's CVD risk factor profile with the primary care physician (PCP) and accompanied the participant on selected office visits. The nurse provided information on guidelines for diabetes, hypertension, dyslipidemia and smoking cessation as needed to participants' physicians, and advocated for evidenced-based monitoring and treatment (19, 53, 81–91). If the participant smoked and was interested in pharmacotherapy, the nurse communicated with the psychiatrist or PCP about prescribing smoking cessation medication and supported the participant through the process. The intervention staff coordinated with mental health staff, therapists, caregivers, physicians and/or office staff to support and reinforce participant health goals. This included facilitating the scheduling of and participant attendance at medical appointments, and removing barriers to obtaining medications and supplies as needed.

## Approaches by Risk Factor

Participants received intervention sessions tailored to their individual CVD risk profiles and readiness to address each risk factor. When participants had multiple risk factors, in keeping with a patient-centered approach, intervention staff worked collaboratively with the participant to identify the focus of the sessions. They used options tools, cards with pictures, for possible conversation topics based on the participant's risk factors (e.g., for someone who smokes and has diabetes the options listed would read: Smoking, exercise, medication, sugar drinks). These tools gave the participant the autonomy to choose specific behaviors to discuss, while also allowing the coach to provide direction to the session.

## Tobacco Smoking Cessation

Intervention staff assessed the motivation of participants who smoke with questions based on the transtheoretical stages of change (92) and placed them in one of three tracks: interested in quitting in 30 days; interested in quitting/reducing smoking but not ready to set a quit date; and expressing no interest in quitting. Those ready to quit within the next month received smoking cessation sessions and those interested but not ready to set a quit date received a motivational enhancement program (19, 93–95). The programs identified personalized reasons to stop smoking, provided training in strategies to respond to urges to smoke (The 4Ds: delay, do something else, deep breathe, drink water), and educated patients about the benefits of quitting and of using smoking-cessation pharmacotherapy. Those in the motivational enhancement program transitioned to quit smoking sessions when ready. These interventions incorporated a breathalyzer that measures expired CO as a marker of recent smoking, with incentives for low CO values. For those willing to consider recommended pharmacotherapy, the nurse worked with participants' physicians to facilitate prescription of varenicline or bupropion, and/or provided dual form nicotine replacement therapy as appropriate. Participants who expressed no interest in quitting smoking focused on other behavior change topics, however, the coach recommended change in smoking behavior monthly and re-assessed willingness to quit. If participants expressed interest in quitting smoking or were ready to set a quit date, they transitioned to another track.

## Diabetes

Intervention staff helped participants optimally manage their diabetes through self-management education sessions, supporting medication adherence, and encouraging selfmonitoring of blood sugar as appropriate. They facilitated hemoglobin A1c monitoring and other guideline concordant care for diabetes with the PCP. For those with uncontrolled diabetes, the nurse and coach coordinated care as needed to decrease barriers to blood glucose control (e.g., obtaining and using glucometer) with mental health staff, caregivers, PCPs and/or specialists. They encouraged high impact dietary behaviors (e.g., no sugar drinks), participation in regular exercise, and weight loss when appropriate.

### Hypertension

The nurse met with participants for hypertension education sessions including discussion of medication adherence. Intervention staff monitored blood pressure regularly and communicated with participants and PCPs about monitoring and treatment goals. The nurse also reinforced the dietary (e.g., avoid salty/processed foods) weight loss and exercise goals set with the coach.

### Dyslipidemia

The nurse met with participants who met recommended guidelines for lipid lowering therapy for medication education and counseling before communicating with the PCP for guideline-concordant treatment. Both the coach and nurse encouraged high impact dietary behaviors (e.g., no greasy foods), participation in regular exercise, and weight loss if needed.

### Overweight/Obesity

The coach used lifestyle strategies that have proven effective in previous clinical trials including individual counseling sessions, weekly weigh-ins, simplified dietary messages (e.g., avoid junk food, avoid sugar drinks, limit snacking, limit portion sizes) and paper trackers to help monitor these behaviors (18). The nurse also linked the roles of weight management to the participant's other CVD risks.

### Unhealthy Diet

Intervention staff provided guidance on ways to eliminate unhealthy dietary choices and incorporate healthier options in the context of other CVD risk factors and the participant's health goals. The conversations used simplified messages and incorporate paper trackers to facilitate awareness and goal setting. Dietary topics included: Avoiding salty/greasy foods, sugar drinks, sweets and processed foods, and eating smart portions and more fruits and vegetables. The coach used role playing and hands-on activities (e.g., visiting the soda machine) to model decision making for healthy diet choices.

#### Physical Inactivity

The intervention staff encouraged participation in regular moderate-intensity physical activity. We trained PRP staff to deliver site-wide group exercise classes using either a study-made DVD or commercially available walking DVD and recommend that classes are offered three times per week. The health coach encouraged exercise class attendance for intervention participants, participated in some of the classes, and substituted for PRP staff if requested. The coach worked with intervention participants to identify additional strategies to meet physical activity recommendations, for example, providing pedometers and setting daily step goals, and providing exercise DVDs to guide home-based workouts. The nurse reinforced exercise goals set with the coach and linked the importance of exercise as an independent health behavior and to the relevant CVD risks.

## DISCUSSION

Given the extraordinarily high and persistent burden of CVD risk factors and resultant CVD in persons with SMI, there is an urgent need for tailored, effective interventions to promote CV health. We describe a comprehensive health behavior coaching and care coordination/care management intervention designed to address each CVD risk behavior and risk factor for adults with SMI in community mental health settings. The IDEAL intervention design has important strengths. First, the intervention uniquely focuses on addressing all of the seven CVD risk factors and behaviors with strategies directed at reaching clinically significant targets consistent with treatment guidelines. Second, the health coach is embedded in the PRP, facilitating coordination and communication with mental health staff in the everyday community mental health outpatient environment. This provides a practical realworld design to optimize future implementation feasibility and sustainability.

The IDEAL intervention faces some challenges to success. The intervention is ambitious in its attempt to address multiple risk factors in persons with SMI given that accomplishing reduction for a single risk factor in those without SMI often takes intensive efforts (96). Fortunately, the intervention's lifestylebased recommendations to help address risk factors such as high blood pressure or high blood glucose involve similar approaches. Having both a coach and nurse use a coordinated approach for each participant should help to address this challenge. Another potential barrier to success is that the intervention team does not prescribe medications, and PCPs in the community have no specific incentive to participate in the intervention's care coordination efforts.

If shown to be effective in the RCT, the IDEAL intervention could be implemented through programs, like the BHH, which provide a financing mechanism for staff (e.g., nurse) and infrastructure to integrate care coordination and management into specialty mental health settings. BHHs are currently operating in 15 U.S. states and D.C. through the Affordable Care Act's Medicaid health home waiver program, and have been implemented through the Substance Abuse and Mental Health Services Administration's Primary Behavioral Health Care Integration initiative and other local programs (35, 36, 38).

However, BHHs generally do not require use of a specific care coordination/management protocol or intervention, thus the strategies currently employed in BHH models vary considerably across sites; they also typically do not emphasize evidencedbased behavioral counseling for CVD risk behaviors (35–44). These features likely contribute to the mixed results to-date for BHHs. The two US RCTs evaluating BHHs found the programs improved quality of primary care delivery; while one showed small reductions in cardiovascular risk among a subset of participants, the second showed no effects on CVD health outcomes (37, 48). These findings suggest that care coordination alone, while potentially capable of improving processes of care, may not be enough to achieve improved clinical outcomes. In Denmark, the CHANGE trial tested care coordination vs. care coordination plus lifestyle coaching vs. control and found no change in CVD risk or individual risk factors over 2 years (97). These null results may be due to the high quality of the health system in Denmark such that many participants at baseline had controlled risk factors; also, the lifestyle coaching may not have been as intense as needed to affect additional CVD risk reduction.

The IDEAL intervention may be well suited for integration into and could improve the effectiveness of models like the BHH. When embedded into a BHH-like structure with its financing, the intervention with its standards of procedure for all aspects of care coordination and tailored, evidenced-based behavioral counseling, could make considerable progress in improving the CVD health for a population that is not routinely receiving quality CV care.

## CONCLUSION

Unless effective interventions that effect CV health outcomes are implemented, populations with SMI will continue to lag far behind the nation's CVD goals. Interventions and models incorporating CVD risk factor treatment in mental health settings to-date have not shown meaningful changes in CV risk factors. The IDEAL intervention incorporates care coordination

## REFERENCES

and care management concepts with intensive health behavior change coaching to address all CVD risks in persons with SMI in community mental health outpatient program settings. If successful, the intervention could be adopted within current integrated care models and significantly improve the physical health of persons with SMI.

## ETHICS STATEMENT

This study was carried out in accordance with the recommendations of the Johns Hopkins Medicine IRB with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by The Johns Hopkins Medicine IRB.

## AUTHOR CONTRIBUTIONS

AD, GD, and GJ wrote the manuscript. GD, LA, GJ, FD, N-YW, DY, JC, RC, AD, SG, JG, CC, EE, and AH contributed to the conception, design and implementation of the study. EM wrote a section of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

## FUNDING

This study has been supported by National Heart Lung and Blood Institute (grant number R01112299) and National Institute of Mental Health (grant number P50115842).

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**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Dalcin, Jerome, Appel, Dickerson, Wang, Miller, Young, Charleston, Gennusa, Goldsholl, Heller, Evins, Cather, McGinty, Crum and Daumit. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# The Influence of Continuous Exercising on Chronotropic Incompetence in Multi-Episode Schizophrenia

Marco Herbsleb1,2, Katriona Keller-Varady <sup>3</sup> , Thomas Wobrock <sup>4</sup> , Alkomiet Hasan<sup>5</sup> , Andrea Schmitt 5,6, Peter Falkai <sup>5</sup> , Holger Horst Werner Gabriel <sup>2</sup> , Karl-Jürgen Bär <sup>1</sup> and Berend Malchow<sup>1</sup> \*

<sup>1</sup> Psychiatric Brain and Body Research Group, Department of Psychiatry and Psychotherapy, University Hospital Jena, Jena, Germany, <sup>2</sup> Department of Sports Medicine and Health Promotion, Friedrich-Schiller-University of Jena, Jena, Germany, <sup>3</sup> Hannover Medical School, Institute of Sports Medicine, Hannover, Germany, <sup>4</sup> Department of Psychiatry and Psychotherapy, County Hospitals Darmstadt-Dieburg, Groß-Umstadt, Germany, <sup>5</sup> Department of Psychiatry and Psychotherapy, University Hospital LMU, Munich, Germany, <sup>6</sup> Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of São Paulo, São Paulo, Brazil

#### Edited by:

Andrea Fiorillo, University of Campania L. Vanvitelli, Italy

#### Reviewed by:

Karl Bechter, University of Ulm, Germany Luigia Trabace, University of Foggia, Italy

\*Correspondence:

Berend Malchow<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Psychosomatic Medicine, a section of the journal Frontiers in Psychiatry

Received: 24 October 2018 Accepted: 07 February 2019 Published: 13 March 2019

#### Citation:

Herbsleb M, Keller-Varady K, Wobrock T, Hasan A, Schmitt A, Falkai P, Gabriel HHW, Bär K-J and Malchow B (2019) The Influence of Continuous Exercising on Chronotropic Incompetence in Multi-Episode Schizophrenia. Front. Psychiatry 10:90. doi: 10.3389/fpsyt.2019.00090 People with schizophrenia die on average 15–20 years earlier than age and gender matched controls in the general population. An essential part of this excess mortality in people with schizophrenia is caused by physical illnesses. Among the physical illnesses, cardiovascular disease (CVD) has been identified as the most common natural cause of death in up to 40–45% of the cases. Chronotropic incompetence (CI) is defined as the inability of the heart to increase its beating frequency in proportion to increased physical activity or higher metabolic demand. It is an established independent cardiovascular risk factor for major cardiac events and overall mortality and might explain adaptation intolerance of the cardiovascular system to even minor exercise courses. CI needs objective exercise testing for definitive diagnosis and therefore represents a biological marker indicating the integrity of the cardiovascular system. It was recently described in patients with schizophrenia and might help explain the reduced physical fitness in these patients and the inability of a subgroup of patients to benefit from exercise interventions. In this study, we tried to replicate the occurrence of CI in an independent sample of patients with schizophrenia and evaluated whether CI can be influenced by a continuous endurance training of 12 weeks. Therefore, we re-analyzed the fitness testing data of 43 patients with schizophrenia and 22 aged and gender matched healthy controls. Parameters of aerobic fitness and chronotropic response to exercise were calculated. Patients with schizophrenia were less physically fit than the healthy controls and displayed a significantly higher heart rate at rest. 10 of 43 patients with schizophrenia and no healthy control subject were classified as chronotropically incompetent. Chronotropic response to exercise did not change significantly after 12 weeks of continuous aerobic exercise training. No differences were observed for baseline heart rate and peak heart rate in both subgroups of schizophrenia patients. Aerobic fitness did not improve significantly in the patients with schizophrenia classified as chronotropically incompetent. Our results confirm the occurrence of CI in patients with multi-episode schizophrenia. This should

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be taken into account when planning an exercise or lifestyle intervention studies in this population. Schizophrenia patients with CI do not seem to benefit as well as schizophrenia patients without CI from aerobic exercise training interventions. Larger, prospective randomized controlled clinical trials with different training interventions are urgently needed to address the topic of schizophrenia patients not responding to exercise and the relationship to the illness itself.

Keywords: schizophrenia, exercise, chronotropic incompetence, cardiac autonomic dysfunction, heart rate response

## INTRODUCTION