Participants

This open trial followed the guidelines of the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement: extension to pilot and feasibility trials (Eldridge et al. 2016). The recruited patients were outpatients at the Bipolar Disorder Program (PROMAN) at the Institute of Psychiatry of the Hospital das Clínicas of the University of Sao Paulo Medical School. All patients were interviewed for the study after providing informed consent. Eligibility criteria included the following: (a) Diagnosis of BD Type I or Type II by Structured Clinical Interview for DSM (SCID-P); (b) Aged between 18 and 55 years; (c) Mild or moderate depressive episode at recruitment - Score on Montgomery–Åsberg Depression Rating Scale (MADRS) ≥ 14 points; (d) No regular PE in the previous six months; (e) Using lithium, quetiapine, valproate, lamotrigine, or a combination of these stabilizers for at least four weeks, without remission of the depressive episode; (f) Patients who were on antidepressants were required to have been taking a stable dose for at least four weeks; (g) No medication change in the four weeks prior to study entry; (h) Patients using a maximum of 2 mg of Lorazepam and/or 10 mg of Zolpidem for insomnia; (i) Body mass index (BMI) ≤ 40. The exclusion criteria were as follows: (a) Being in a manic or hypomanic episode at recruitment - Score on the Young Mania Rating Scale (YMRS) > 12 points; (b) having an organic mental disorder; (c) Abuse of alcohol or illicit drugs in the previous two weeks; (d) Using of beta-blocker.

Study design and procedures

This study was a prospective, single-center, open-label, single-arm pilot trial conducted from December 2016 to March 2020. As this is a pilot study, no sample size calculations were performed. Before enrollment, informed consent was obtained from all patients and the local ethics committee approved the study (protocol number 3.119.424). This study was conducted by the Declaration of Helsinki (Goodyear et al. 2007). Individualized and supervised training sessions of aerobic plus strength training (added to pharmacological treatment), were performed three times a week (Monday, Wednesday, and Friday) for 12 weeks (36 training sessions).

All patients were diagnosed with BD type I or II based on the Structured Clinical Interview for DSM IV (SCID-P) (First and Gibbon 2004) and followed in the outpatient service for at least one year before the beginning of this study. In addition, symptoms of depression (MADRS) and mania (YMRS) were assessed at baseline and after 2, 4, 8, and 12 weeks. In relation to MADRS scores, we followed the categories of depression severity in patients with BD (mildly depressed - until 18 points, moderately depressed – 19–23 points, markedly depressed – 24–36 points, severely depressed – 37–39 points, and, extremely depression ≥ 40 points) defined by Thase et al. (Thase et al. 2021). Finally, Functioning (Functioning Assessment Short Test - FAST) and Quality of Life (World Health Organization Quality of Life - WHOQOL-bref) were assessed at baseline and after 4, 8, and 12 weeks. The MADRS and YRMS scales are scales typically used in interventions in patients with BD (assessing symptoms of depression and mania) (Montgomery and Asberg 1979; Young et al. 1978). The FAST is an instrument designed to measure functioning disability and validated in patients with BD (Rosa et al. 2013). The WHOQOL-bref is an instrument developed to assess Quality of Life (Whoqol-Group, 1998).

At baseline, patients were evaluated by a clinical physician in order to assess musculoskeletal disorders, cardiovascular disorders and measure vital signs. If necessary, supplementary laboratory testing was ordered prior to approving the patient to participate in the physical exercise program. The physical fitness test (cardiorespiratory fitness, muscular strength and body composition) was assessed at baseline and after 12 weeks.

Physical fitness test – cardiorespiratory fitness, muscular strength and body composition

Ergospirometry test mensured cardiorespiratory fitness (peak oxygen uptake - VO2peak) used a treadmill (H/P/Cosmos Sports & Medical, Nussdorf-Traunstein, Germany), and was conduced modified Heck protocol (Heck et al. 1985; Santos-Silva et al. 2007), ramp style, with fixed speed and 2% incline increments every minute. The total exercise time test lasted between 8 and 15 min, as previously described in the literature (Buchfuhrer et al. 1983). The cardiac response to the incremental was used as parameter of cardiac health (electrocardiographic signal was recorded throughout the test).

Muscular strength, was measured by the one repetition maximal test (1RM). In resume, a unilateral leg press 45° 1RM testing were performed considering the American Society of Exercise Physiologists’ recommendations (Brown and Weir 2001). The participants ran for 5 min (min) on a treadmill, followed by two warm-up sets. In the first set, the participants performed eight repetitions with an intensity of 50% of their estimated 1RM obtained during the familiarization sessions. In the second set, they performed three repetitions with 70% of their estimated 1RM. A 3-min rest interval was afforded between warm-up sets. After completing the second set, participants rested for 3 min and then had five attempts to achieve their 1RM. Again, a 3-min rest interval was afforded between attempts (Brown and Weir 2001). Finally, percentage of body fat and body muscle mass was measured using a spectral bioelectrical impedance analysis (InBody 270, Biospace Seoul, Korea). In resume, the subjects were instructed to fast for at least three hours, not to perform physical activity the day before the exam, and not to drink alcoholic beverages, coffee, tea, chocolate, and soft drinks.

Program of exercise

The following exercises were completed under supervision: Aerobic training (treadmill); strength training (specific equipment).

Aerobic training

Aerobic training on a treadmill (H/P/Cosmos Sports and Medical, Nussdorf-Traunstein, Germany) consisted in 5 min at 65–70% of heart rate maximum (HRmax), 20 min at 70–85% of HRmax, and 5 min at 65–70% of HRmax.

The intensity was based on a percentage of the HRmax, which was checked in ergospirometry test. All patients used in all section of training a heart rate monitor (Polar H7, Polar Electro Oy, Kempele, Finland) with Polar Beat.

Strength training

The protocol consisted of five exercises [Leg press, Leg extension, Seated crunch machine (abdominal), Bench press, and Rower machine], with specific equipment (Multiflex, Biodelta®, Brazil), been realized by three sets of 15 repetitions with one to two minutes intervals.

The strength training during the first two weeks, self-selected loads were used due to the need to learn the movement. After this period, loads of 15 repetitions were used, and in each training session, if the subject was able to perform more than 15 repetitions, the load was adjusted.

Statistical procedures

The data were analyzed using IBM SPSS Statistics, version 22 (SPSS Inc., Chicago, IL, USA). Data are described as individual values. The mean scores (+- SD – standard deviation) of eleven patients and groups are presented. The Cohen’s D Effect Size (Cohen 2013) – [Cohen’s d = (M2 - M1) ⁄ SD pooled] [SD pooled = √ ((SD1 + SD2) ⁄ 2)] with 95% confidence interval (CI) was used to determine the magnitude of the difference detected between baseline and 12 weeks. The interpretation of effect size (ES) used was: 0 to < 0.30 | small, |> 0.30 | to | <0.8 | medium, and |> 0.80 | large. As this is a feasibility study, a formal sample size calculation was not performed.