Effects of an Acute Maximal Exercise Bout on Serum Insulin-Like Growth Factor-1 in Adults with MDD

Abstract

Exercise has acute, positive effects on mood and can lead to antidepressant effects over time when repeated regularly. The mechanisms underlying the antidepressant effects of exercise training are not well known, limiting the prescription of exercise training for depression. Serum Insulin-Like Growth Factor-1 (IGF-1) appears dysregulated in those with Major Depressive Disorder (MDD), suggesting MDD could inhibit or alter the IGF-1 response to exercise. In healthy individuals, exercise has been shown to acutely increase serum IGF-1, which may act positively on the dysregulated IGF-1 system in MDD. Therefore, the purpose of this study was to examine the sensitivity of serum IGF-1 levels to an acute maximal exercise bout in adults with MDD and healthy controls. Additionally, clinical and behavioral factors of MDD are likely to affect this system, such as depression severity, antidepressant usage and physical activity habits.

Baseline data were used from a larger trial in Germany (SPeED Study) collected from individuals with mild to moderate MDD (n=113) and healthy controls (n=34) that were matched for age, sex, and education. Demographics, depression severity (Hamilton Depression Rating Scale-17), self-reported antidepressant usage, MVPA (International Physical Activity Questionnaire-Short Form), and blood draws before and after a maximal exercise test were collected. Multiple linear regressions were conducted to determine relationships between depression severity, antidepressant usage, and physical activity with peripheral IGF-1 levels following acute exercise. Covariates included demographic factors and IGF-1 pre-exercise (baseline levels).

Acute IGF-1 changes occurred similarly in depression (mean ± SD; 11.3 ± 12.9) as well as healthy adults (11.3 ± 20.4: p>0.05). Neither depression severity, antidepressant use, nor regular physical activity were significant predictors of peripheral IGF-1 levels at baseline or following exercise.

Individuals with MDD are likely to have favorable exercise-induced IGF-1 changes regardless of clinical and behavioral differences. Acute exercise increases peripheral IGF-1 briefly, and in response to repeated exercise bouts, the IGF-1 system could normalize over time. The normalization of the IGF-1 system might be a possible mechanism underlying mood increases that occur during exercise with exercise training research warranted.

1. INTRODUCTION

Depression affects 5% of people worldwide and is the leading contributor to disability and the global burden of disease (World Health Organization, 2021). Only 60–70% of patients show a clinical response to antidepressant medication (Al-Harbi, 2012) and 50% or fewer of those taking antidepressants or undergoing therapy enter remission (Szczęsny et al., 2013). Exercise has been shown to reduce depressive symptoms, improve mood in depressed individuals, and could be as effective as common treatments (i.e., psychotherapy and medication; Heissel et al., 2023; Noetel et al., 2024; Singh et al., 2023). Although mood improvements have been shown with both single sessions of exercise (referred to as acute exercise herein) and exercise training (e.g., repeated bouts of exercise, referred to as chronic exercise herein), the neurobiological mechanisms underlying exercise’s antidepressant effects are still largely unknown.

Past literature suggests several mechanisms are disrupted or altered in major depressive disorder (MDD): serotonergic, noradrenergic, dopaminergic, glutaminergic systems, increased inflammation (Miller & Raison, 2015) and stress responses (Dean & Keshavan, 2017). Interindividual variability in underlying causes of MDD and severity between patients makes identifying mechanisms and optimizing treatment difficult. Further exploration of potential mechanisms and potential alternative/adjunctive treatments is needed to increase treatment effectiveness. During acute exercise, many biological and physiological systems are affected – indicating the potential viability of exercise as a treatment for MDD.

Exercising regularly can influence candidate blood biomarkers related to depression (Maass et al., 2016) and can lead to acute (Meyer et al., 2016) and chronic (Noetel et al., 2024) improvements in symptoms of depression. Due to the effects exercise has throughout the body, many systems are likely to be positively impacted with exercise – potentially making exercise a more consistent antidepressant option regardless of individual differences in pathophysiology of MDD. Though exercise has consistent physical and mental health benefits (Maass et al., 2016; Meyer et al., 2016; Noetel et al., 2024), it is not widely used for MDD treatment, potentially due to a lack of clear knowledge about the mechanisms underlying its antidepressant effect. Therefore, understanding exercise’s effects on depression-relevant biomarkers may aid in further understanding the antidepressant effect of exercise.

Insulin-like growth factor-1 (IGF-1) appears to be a potentially useful, depression-relevant biomarker that is also exercise-responsive. Primarily produced in the liver, IGF-1 has important downstream functions in the hippocampus, such as neurogenesis and neuroplasticity (Szczęsny et al., 2013). After the liver releases IGF-1 peripherally, binding proteins (IGFBP 1–6) carry IGF-1 to various tissues in the body, before it binds to the IGF-1 receptor (IGF-1R; Higashi et al., 2012). Depression can produce a chronic stress response that is manifested via high levels of cortisol and pro-inflammatory markers that lead to increased peripheral IGF-1 and thus reduced hippocampal size (Brown et al., 2016). These hippocampal brain structure changes lead to reduced memory, limbic system dysfunction, and are associated with a reduced response to antidepressant treatment (Brown et al., 2016). Understanding how the IGF-1 system may be influenced by an acute exercise bout is needed to understand IGF-1 system dysregulation in MDD.

However, chronic exercise may down-regulate the IGF-1 system in individuals with MDD (Borba et al., 2020). Repeated exposure of exercise-induced IGF-1 changes may bring the IGF-1 system under control, leading to slowed or even reversed hippocampal degradation (a known effect of exercise in MDD; Maass et al., 2016). These effects of exercise on the IGF-1 system may play a potential role in the antidepressant effect of exercise. Additionally, exercise may have an important role in serum IGF-1 regulation as past research has shown increased release of IGF-1 via muscle stores during and immediately following exercise (Borba et al., 2020). Speculatively, this increased release may assist in the antidepressant effect of exercise and, over time, lead to increased muscle storage capacity and further central down-regulation. Common clinical and behavioral differences in MDD, such as depressive symptom severity, antidepressant usage and regular physical activity (defined as any bodily movement that results in energy expenditure; Caspersen et al., 1985), may result in variations in the responsiveness of the IGF-1 system to external stimuli (e.g., exercise). However, the effects of antidepressant usage and participation in regular physical activity on the acute IGF-1 response to exercise are not yet known.

The present study aims to examine serum IGF-1 responses to acute maximal exercise in those with depression compared to healthy adults while also considering clinical and behavioral differences. Past research suggests IGF-1 increases with acute exercise, although dysregulation in the IGF-1 system in depression may alter this response. Second, understanding the associations between potential clinical and behavioral causes of interindividual variance (e.g., variation in IGF-1 responsiveness by depression severity (Aim 1), antidepressant usage (Aim 2), and physical activity participation (Aim 3) is important for identifying candidate factors that could influence the adaptability to exercise over time.

2. METHODS

The present analysis comes from baseline fitness testing and associated measurements of the larger SPeED study (Sport/Exercise Therapy and Psychotherapy-evaluating treatment Effects in Depressive patients) performed in Berlin, Germany (Heinzel et al., 2018, 2022). This study was a randomized controlled trial designed to investigate the effects of an exercise intervention on the success of subsequent cognitive behavioral therapy (CBT) in MDD. The overall study was a 3-month exercise intervention followed by a 3-month psychotherapy intervention. Data from the initial baseline visit (t1) were used to perform the present analysis. Methods reported are specific to this analysis unless otherwise noted.

2.1. PARTICIPANTS

At baseline, (n=147) participants completed multiple assessments including a sports medical examination, with n=113 diagnosed with MDD and n=34 healthy controls (see Table 1). Participants were recruited through the Center for Psychotherapy at Humboldt University in Berlin, Germany along with flyers and online advertisements. Methods reported are part of a larger study designed to determine the effects of 3 months of chronic exercise in those with Major Depressive Disorder (MDD) prior to receiving 3 months of cognitive behavioral therapy (CBT; SPeED Study). Inclusion criteria were as follows: diagnoses of mild or moderate depressive episode, 18–65 years old, and passing a sports medical examination including an electrocardiogram done during a cycle ergometer test, performed until meeting test termination criteria (Borg, 1982; Heinzel et al., 2018). Mental health, past and present, was assessed using the German version of the Structured Clinical Interview for DSM-IV TR (SCID, First, 2015). Trained psychologists performed all mental health exams. Exclusion criteria were as follows: borderline or antisocial personality disorder, current suicidality, a body mass index of <18 or >35, magnetic resonance imaging unsuitability, use of benzodiazepines or beta-blockers within the last 7 days, >2×45 minutes of vigorous physical exercise per week. The study protocol was approved by the local ethics committee of Charité Universitätsmedizin Berlin, Germany (No EA1/113/15), and informed consent was provided by all participants (Heinzel et al., 2022).

Table 1.

Characteristics of Participants

Characteristic	MDD Mean (sd)	HC Mean (sd)
Age (years)	39 (10)	37 (13)
Body Mass Index (kg/m2)	25 (4)	25 (4)
Hamilton Rating Scale for Depression Total	13 (4)	1 (1)
Beck Depression Inventory Total	27 (8)	1 (2)
Brief Symptom Inventory Depression Total	2 (1)	0 (0)
Brief Symptom Inventory Anxiety Total	1 (1)	0 (0)
Beck Anxiety Inventory Total	17 (9)	3 (6)
Dysfunctional Attitudes Scale Total	147 (35)	95 (20)
IGF-1 (ng/mL)
Pre-Exercise	210 (53)	226 (51)
Post-Exercise	221 (53)	237 (53)
Sex	n (Percentage)	n (Percentage)
Male	59 (40)	14 (9)
Female	54 (37)	20 (14)
Hamilton Rating Scale for Depression Total
Mild (8–16)	86 (63)
Moderate (17+)	17 (12)
Antidepressant Use
SSRI	21(14)
Other	22 (15)
MDD w/no use	70 (48)
Activity Level
Inactive	25 (22)
Minimally Active	64 (57)
HEPA	23 (21)

Note: HAM-D categories based on the 17-item version, n=173 - see exclusionary criteria. HEPA: Health Enhancing Physical Activity. Inactive (0 – 599 MET min/wk), Minimally Active (600 – 2999 MET min/wk), HEPA (3000+ MET min/wk). Activity Level analysis included only individuals with MDD (n=112). All means and standard deviations rounded to the nearest whole number.

2.2. MEASURES

2.2.1. Exercise Protocol.

A graded exercise test on a cycle ergometer was used to assess physical fitness. Starting at 25 W with an increased workload by 25 W every 2 minutes was used until participants were physically unable to continue. Test termination criteria were: being physically unable to continue, defined as maximum exhaustion, or critical event occurrence. The workload was then normalized to Watts per Kilogram by dividing maximal effort watts by the participant’s body weight. The protocol utilized was from the World Health Organization protocol as recommended by the German Society of Cardiology (Trappe & Löllgen, 2000) and reported in the guidelines of the American Heart Association (American Heart Association, 2023). This test was monitored through electrocardiogram (ECG), blood pressure measurements, Borg’s rating scale of perceived exertion (RPE; Borg, 1982), with lactate measures prior to starting the test, at the end of each 2-minute level, at the termination of the test, and 3- and 5-minutes following completion. To ensure safety, the test was monitored by a sports physician.

2.2.2. Blood Sample Collection & Storage.

As reported in Kallies et al. (2019), blood samples were collected from non-fasting participants in a supine position via intravenous blood draw. Participants rested for at least 20 minutes before the blood draw. Serum tubes were used for IGF-1 analysis and were set to clot for 60-minutes at room temperature before being centrifuged for 10 minutes at 1300 × g and 20 degrees Celsius. Serum was then obtained in microliter tubes and stored at −30 degrees Celsius prior to final analysis. Blood draws post-exercise were taken 5 minutes after the completion of the exercise test and handled as outlined above.

2.2.3. Sample Analysis.

Serum IGF-1 was measured with a highly sensitive and specific fluorometric two-site enzyme-linked immunosorbent assays (ELISA) according to the manufacturer’s instructions (Promega Inc., Mannheim Germany). Analyses were performed in triplicate and results were averaged. All pre-and post-exercise serum IGF-1 analyses were performed using the same assay to reduce potential inter-assay variation.

2.2.4. Depression.

The 17-item clinician-administered Hamilton Rating Scale for Depression (range: 0–52) (HAM-D, Hamilton, 1986) was used to assess depressive symptoms across the population by a trained interviewer; higher scores indicated higher severity of depression. Participants were categorized based on their sum scores: normal (0–7), mild depression (8–16), moderate depression (17–23) and severe depression (24–52). Depression status for inclusion in the study was categorized based on the SCID. Due to this method of categorization, 10 individuals with a HAM-D score of 0–7 were included in the overall study, although their current depressive symptoms would be categorized as normal on the HAM-D, thus these individuals were removed from the analysis (n=137) per the HAM-D categorization guidelines (Hamilton, 1986). Those with high-severity depressive symptoms were excluded from the overall study, therefore the sample only included those with mild and moderate severity depression.

2.2.5. Mental Health.

Additional mental health questionnaires were administered to further assess depressive symptoms and other comorbid mental health disorders. These questionnaires included the Beck Depression Inventory (Beck et al., 1996), Brief Symptom Inventory (Derogatis & Melisaratos, 1983), Beck Anxiety Inventory (Beck et al., 1988), and Dysfunctional Attitudes Scale (Weissman, 1979). For each of the above assessments, standard scoring was used for totals and subscales in accordance with each citation.

2.2.6. Physical Activity.

The International Physical Activity Questionnaire (IPAQ, Craig et al., 2003) was used to assess self-reported moderate to vigorous physical activity (MVPA). In accordance with standard recommended rules, participants were categorized based on their combined MET minutes per week as inactive (0–599 MET mins/week), minimally active (600–2999 MET mins/week), or health-enhancing physical activity (HEPA; 3000+ MET mins/week; Fogelholm et al., 2006).

2.3. STATISTICAL ANALYSIS

Analyses were performed using R software (R Core Team, 2021; Version 4.2.1). Participant characteristics were described using means and standard deviations for continuous variables and proportions for categorical variables. Demographic and exercise exposure (MDD vs healthy control) differences were tested via t-test to confirm statistical power needed to compare these groups and ensure the exercise exposure was statistically the same for both groups. For aim 1, groups were defined using depression severity on the HAM-D scale (mild, moderate, and healthy control); linear regression was used to model IGF-1 serum differences among groups before and after exercise. For aim 2, groups were defined based on antidepressant use (SSRI, other antidepressants, not using antidepressants, and healthy controls); linear regression was used to model IGF-1 serum differences among antidepressant groups before and after exercise. For aim 3, groups were defined using IPAQ data (inactive, minimally active, HEPA); linear regression was used to model IGF-1 serum differences among activity groups before and after exercise. Post hoc pairwise comparisons and Cohen’s d effect sizes were used to determine the significance of differences between groups. Cohen’s d effect sizes were evaluated using standard methods as small (around 0.20), moderate (around 0.50) or large (around 0.8) effects (see Cohen, 2013). Due to the ordered nature of the groups a linear trend term was added to models for aims 1 and 3. In all models, age, sex, and pre-exercise IGF-1 levels were included as covariates.

3. RESULTS

3.1. ACUTE EXERCISE EVALUATION

Overall, the maximal exercise test lasted an average of 11.6 minutes, with participants reaching an average of 19.6 RPE and an average heart rate of 172.8 beats per minute. The average maximal power output of the sample was 2.27 watts per kilogram of body weight. Across the exercise bout, individuals with MDD and those in the healthy control group did not have statistically significant differences in the maximal exercise bout time (p=0.94), RPE (p=0.81), heart rate (p=0.92), or power output (p=0.50; see Table 2).

Table 2.

Exercise Condition Characteristics.

	MDD Mean (sd)	HC Mean (sd)
Maximal Exercise Test Duration (minutes)	11.6 (3.0)	11.7 (3.1)
Peak Rating of Perceived Exertion	19.6 (0.9)	19.6 (0.9)
Peak Heart Rate (beats per minute)	173.0 (15.6)	172.4 (15.2)
Peak Power (Watts/Kg)	2.25 (0.52)	2.33 (0.58)

Note. Rating of Perceived Exertion was based on the (Borg, 1998) scale ranging from 6–20; Peak Power was calculated using maximal watts in the exercise condition divided by the participants weight in Kilograms

3.2. INSULIN-LIKE GROWTH FACTOR-1 CHANGES

At baseline (before exercise), depression status (p=0.36) and sex (p=0.98) were not significant predictors of IGF-1 levels. However, age had a significant negative relationship with IGF-1 levels (p<0.001), indicating lower IGF-1 levels with age. Depression status was not a significant predictor of post-exercise IGF-1 (p=0.82) and was not significantly related to person-level variables of age (p=0.16) or sex (p=0.15). Baseline IGF-1 was predictive of post-exercise IGF-1 (p<0.05) in all analyses. Mean differences for IGF-1 were small between groups MDD (pre-exercise: 209.6 ± 52.8; post-exercise: 220.8 ± 53.2; See Table 3) and healthy controls (225.5 ± 50.9; 236.8 ± 52.8) both pre-and-post exercise (d=0.02), though the overall change in response to exercise was large (11.3 ± 12.9 ng/mL, d=0.87; see Figure 1).

Table 3.

Insulin-Like Growth Factor Changes.

		IGF-1 Pre-Exercise (ng/mL)		IGF-1 Post-Exercise (ng/mL)		IGF-1 Change (ng/mL)
		Mean	SD	Mean	SD	Mean	SD
Overall Differences	MDD	209.56	52.80	220.82	53.15	11.27	12.93
	Healthy Control	225.48	50.85	236.77	52.78	11.29	20.40
Aim 1 - HAM-D Total	Mild	211.48	50.75	223.48	50.47	11.88	13.56
	Moderate	216.55	57.39	227.23	57.62	10.69	10.45
	Healthy Control	225.48	50.85	236.77	57.78	11.29	20.40
Aim 2 - Antidepressant Usage	SSRI	188.28	43.57	200.14	43.26	11.86	12.53
	Other	198.70	57.01	212.40	60.78	13.71	10.73
	None	219.35	52.09	229.67	51.84	10.32	13.71
Aim 3- Physical Activity	Inactive	206.88	55.40	213.16	53.93	6.28	11.76
	Minimally Active	210.27	53.76	223.63	53.22	13.36	13.14
	HEPA	208.33	49.46	219.51	54.10	11.18	12.75

Note. HAM-D categories based on the 17-item version, n=173 - see exclusionary criteria. HEPA: Health Enhancing Physical Activity. Inactive (0 – 599 MET min/wk), Minimally Active (600 – 2999 MET min/wk), HEPA (3000+ MET min/wk)

Figure 1. Line Graph of Exercise-Induced IGF-1 Changes by Group.

Note. Line graph presenting mean ± standard deviation differences in IGF-1 changes (ng/mL) between groups before and after an acute maximal exercise bout.

3.3. DEPRESSION SEVERITY (AIM 1)

At baseline, depression severity (p=0.70) and sex (p=0.83) were not significant predictors of IGF-1 levels. However, age had a significant, negative relationship with IGF-1 levels (p<0.001). Depression severity was not a significant predictor of post-exercise IGF-1 (p=0.97; See Table 4). There were no significant pairwise differences between mild severity, moderate severity, and healthy controls (all p>0.05) or a significant linear trend across groups (p=0.81). Depression severity was not a significant predictor of post-exercise IGF-1 (p=0.97). There were no significant pairwise differences between mild severity, moderate severity, or healthy controls (p>0.05) or significant linear trend across groups (p=0.50). Mean differences for IGF-1 pre-and-post exercise were all small (all d<0.20; see Figure 2).

Table 4.

Linear Regression Model Results.

	IGF-1 Post-Exercise
	DF	β (SE)	p	Effect Size	95% Effect Size Confidence Interval
Model 1 (Depression Severity)	131
Healthy Control		REF	REF	REF
Mild Depression		−0.13 (3.11)	0.97	0.01	−0.40, 0.42
Moderate Depression		−1.09 (4.51)	0.81	0.07	−0.52. 0.66
Age		−0.18 (0.15)	0.22
Sex		−2.81 (2.61)	0.29
IGF-1 Pre-Exercise		0.94 (0.03)	<0.001
Model 2 (Antidepressant Usage)	140
Healthy Control		REF	REF	REF
SSRI		0.20 (4.26)	0.96	−0.01	−0.58, 0.55
Other		1.33 (4.23)	0.75	−0.09	−0.65, 0.47
No Antidepressant		−1.41 (3.13)	0.65	0.09	−0.32, 0.51
Age		−0.22 (0.14)	0.14
Sex		−3.28 (2.51)	0.19
IGF-1 Pre-Exercise		0.95 (0.03)	<0.001
Model 3 (Physical Activity)	106
HEPA		REF	REF	REF
Inactive		−4.35 (3.76)	0.25	0.34	−0.25, 0.93
Insufficiently Active		2.93 (3.09)	0.35	−0.23	−0.72, 0.25
Age		−0.09 (0.15)	0.55
Sex		−4.59 (2.42)	0.06
IGF-1 Pre-Exercise		0.96 (0.03)	<0.001

Note: HAMD Categories: 0–6 (Healthy Control), 7–14 (Mild Depression Severity), 15+ (Moderate Depression Severity). HEPA: Health Enhancing Physical Activity. Inactive (0 – 599 MET min/wk), Minimally Active (600 – 2999 MET min/wk), HEPA (3000+ MET min/wk)

Figure 2. Boxplots of IGF-1 Change between Linear Analysis Groups by Aim.

Note. Boxplots presenting mean differences in IGF-1 changes (ng/mL) between groups based on depression severity (A), antidepressant usage (B) and activity level (C).

3.4. ANTIDEPRESSANTS (AIM 2)

At baseline, antidepressant usage (p=0.54) and sex (p=0.98) were not significant predictors of IGF-1 levels. However, age had a significant, negative relationship with IGF-1 levels (p<0.001). There were no significant pairwise differences between SSRIs, other antidepressants, no antidepressants, and healthy control groups (all p>0.05). Antidepressant usage was not a significant predictor of post-exercise IGF-1 levels (p=0.89). There were no significant pairwise comparisons between SSRIs, other antidepressant, no antidepressants, and healthy controls (all p>0.05). Mean differences in IGF-1 pre-and-post exercise were small (all d<0.40; See Figure 2).

3.5. PHYSICAL ACTIVITY (AIM 3)

At baseline, activity level (p=0.27) and sex (p=0.95) were not significant predictors of IGF-1 levels. However, age had a significant, negative relationship with baseline IGF-1 levels (p<0.001). There were no significant pairwise differences between those reporting inactive, minimally active, and HEPA (all p>0.05) and no significant linear trend across groups (p=0.74). Activity level was not a significant predictor of post-exercise IGF-1 (p=0.06). There were not significant pairwise differences between inactive, minimally active and HEPA (all p>0.05) and no significant linear trend across groups (p=0.35). Those reporting to be minimally active had a moderately larger IGF-1 change compared to those reporting to be inactive (d=0.58), while all other comparisons were small (all d<0.34; See Figure 2).

4. DISCUSSION

This study aimed to investigate changes in serum IGF-1 in response to an acute maximal exercise bout in 113 individuals with mild to moderate MDD and 34 healthy controls while considering the effects of depression severity, antidepressant usage, and chronic physical activity habits on exercise-induced serum IGF-1 changes. The present study found that those with MDD did not differ from age-matched healthy controls in baseline IGF-1 levels nor in response to a maximal, acute bout of exercise. Past literature indicates that a moderate-intensity exercise bout increases IGF-1 levels (Berg & Bang, 2005), which may lead to increased downstream signaling to target tissues (e.g., the hippocampus) and greater central functioning of IGF-1. The present findings from a large sample of addressed adults and matched controls indicate that peripheral IGF-1 acutely increases after acute maximal exercise in those with MDD, similar to what was seen in healthy individuals.

Past literature indicates individuals with depression tend to have higher baseline levels of circulating IGF-1 compared to age-matched healthy individuals (Kopczak et al., 2015). However, in the present study including 147 total participants, there was a limited difference between individuals with MDD and age-matched healthy controls at baseline (d=0.18) and essentially no difference in exercise-induced changes between the two groups (d=0.05). Elevated peripheral IGF-1 levels have been found previously in MDD (Kopczak et al., 2015), but interindividual differences in depression and depression severity may influence the differences in the IGF-1 system that are present in these results (Arinami et al., 2023). Thus, the exclusion of individuals with severe depression symptoms in the present study may explain the lack of difference between the present depressed and healthy groups. Participants in Arinami et al., 2023 had a similar average HAM-D to the present trial (13 vs 13), while more severe groups have also been studied (e.g., in Kopczak et al., 2015). In both Arinami et al., 2023 and Kopczak et al., 2015, there were significant differences in baseline serum IGF-1 values in individuals with MDD compared to controls, despite differences in depression severity. Incorporating our present results, these findings indicate that depression severity may play a role in baseline IGF-1 levels, however other factors should be explored in future research to determine other potential causes of IGF-1 differences. The lack of observed baseline differences paired with the observed increases in peripheral IGF-1 post-exercise suggest that the IGF-1 system can be positively influenced by acute exercise in individuals with MDD. Importantly, these results indicate that the acute functioning of exercise-induced IGF-1 changes is similar in healthy adults and individual’s with MDD. Therefore, if IGF-1 changes may elicit an antidepressant effect and can be modulated with exercise, chronic exercise may have important effects on IGF-1 in MDD that should be explored for potential long-term mental health benefits.

Antidepressant medications, particularly SSRIs (Mosiołek et al., 2021), have been found to lower peripheral IGF-1 levels while increasing central functioning of IGF-1 (Bot et al., 2016; Kopczak et al., 2015; Levada & Troyan, 2017), but little is known about how antidepressant usage affects expected exercise-induced IGF-1 system changes. In the present study, antidepressant status was not significantly associated with IGF-1 levels at baseline (all d<0.39) or after an acute bout of exercise (all d<0.18). Although this analysis provides different findings than past literature, many of the previous studies show differing results to one another after antidepressant treatment (Kopczak et al., 2015; Levada & Troyan, 2017). Additionally, those recruited for the present study were on low doses of antidepressants and groups had small sample sizes (SSRI (n=19), other antidepressants (n=21), no antidepressants (n=63)) due to low rates of prescriptions for antidepressants in Germany, potentially leading to the differences in findings compared to previous literature. Participants from previous studies reported higher rates of antidepressant use (Arinami et al., 2023; Kopczak et al., 2015) and showed mixed results, but in a study that prescribed antidepressants to non-users (Levada & Troyan, 2017), there was a down-regulation of IGF-1. Incorporating our present results, these findings indicate that additional characteristics of antidepressant usage beyond type (e.g., duration, number of medication courses, etc.) may be important for future research to consider. The lack of antidepressant influence on the IGF-1 response to exercise suggests that exercise, even in adults taking antidepressant medications, may be able to normalize inflammation and the pathophysiology of MDD.

Regular physical activity has been able to decrease peripheral IGF-1 levels to normative values in MDD (Eliakim & Nemet, 2010). In the present study, compared to self-reporting being inactive, those who self-reported being minimally active did not have significantly different baseline (d=0.35) or post-exercise IGF-1 (d=−0.58). These effect sizes are indicative of a small-to-moderate relationship between exercise and IGF-1 changes, although the variance of directionality indicates a potential non-linear (or spurious) relationship that warrants further evaluation. This acute change in IGF-1 may be related to the short-term mood effects that have been shown to occur following exercise (Meyer et al., 2016), although these were not recorded in the present study and should be explored in the future. While regular physical activity may lead to long-term regulation of IGF-1 in MDD (Eliakim & Nemet, 2010), the present study shows that regardless of how generally physically active an individual reports being, there appears to be a consistent acute IGF-1 response to exercise.

There are additional functions of the IGF-1 system that may have led to the present findings. Perhaps the functioning of the IGF-1 system in MDD is affected, not through antidepressant use, depression severity, or lifestyle factors (e.g., regular exercise) but a reduction in the downstream cellular signaling in the hippocampus (Krogh et al., 2014). Findings in the present study indicate the potential for serum IGF-1 levels in individuals with MDD to be comparable to that of age- and sex-matched individuals without MDD, at both baseline and after acute exercise. Thus, if decreased hippocampal neurogenesis is occurring in this population, the issue may not be the amount of peripheral serum IGF-1 present, but within the downstream cellular signaling (Krogh et al., 2014). Past literature has indicated the negative effects of a blocked downstream IGF-1 cellular signal, but has shown that a long-term exercise intervention may reduce or even reverse the negative impacts caused by reduced IGF-1 signaling (Maass et al., 2016). Due to the limited extant research of the IGF-1 system in MDD, future research should consider the potential exercise-induced IGF-1 changes occurring both centrally and peripherally in those with MDD.

Lastly, it is important to note that IGF-1 may be a key component of the antidepressant effect of exercise but should be considered in the context of other psychobiological changes that also occur with exercise in MDD. Simultaneously, depression is highly heterogeneous, which highlights the need for further investigation into biomarkers of the disease and treatment response. There are a few psychobiological mechanistic hypotheses of the antidepressant effect of exercise, such as regulation of the monoaminergic system (Cowen & Browning, 2015; Dean & Keshavan, 2017; Krishnan & Nestler, 2010; Lin & Kuo, 2013), hypothalamic-pituitary-adrenal axis (Archer et al., 2014), endocannabinoids (Heyman et al., 2012), and increased brain-derived neurotropic factor (Heyman et al., 2012). However, exercise prescription for MDD treatment remains uncommon, likely due to the necessity of further understanding the precise role of concrete mechanisms of action. By better understanding the underlying neurobiological underpinnings of MDD and how these biomarkers are associated with one another, future MDD treatments (exercise-based or otherwise) have the opportunity for increased success.

Strengths of the present study include the use of age and sex-matched healthy controls that allow for differences to be detected without the effect of age or sex-related IGF-1 differences between the two groups. However, there are also limitations to the present study. First, many of the groups were not balanced for size, somewhat limiting power compared to a fully balanced design. Indeed, some analyses groups were limited in numbers (i.e., antidepressants groups) and the accompanying results should be interpreted cautiously. Next, an acute increasing-intensity maximal exercise bout of 12–15 minutes may not be enough to see depression-pathophysiology-relevant differences in IGF-1 responsiveness between individuals. Thus, a longer or intensity-standardized exercise bout should be considered in the future to examine acute IGF-1 responsiveness to exercise further in this population. Finally, the IPAQ is a self-reported measure that may lead to over-reporting or under-reporting of one’s physical activity, although it has been validated globally (IPAQ Research Committee, 2005). Thus, results should be interpreted with caution.

5. CONCLUSION

Exercise-induced increases in IGF-1 were large (11.3 ± 12.9 ng/mL) and similar across participants regardless of depression severity, antidepressant usage/type, and chronic physical activity differences. The lack of differences between these groups indicates that adults with MDD are likely to have favorable exercise-induced IGF-1 increases, suggesting healthy responsiveness of the IGF-1 system to exercise in MDD. As these IGF-1 changes occurred regardless of major clinical and behavioral differences, a broad recommendation of exercise during treatment for adults with MDD is encouraged along with future research unraveling how the IGF-1 system responds to chronic exercise in adults with MDD.

Highlights:

• IGF-1 change after maximal exercise did not differ between MDD or healthy controls

• Physical activity, antidepressant use, nor depression severity affected changes

• Compared to inactive, minimally active adults had a moderately higher IGF-1 change

• Clinical and behavioral differences do not affect IGF-1 change in MDD in this sample

• Exercise-induced IGF-1 changes were large across both MDD and healthy controls