Exercise Intervention in Individuals at Clinical High Risk for Psychosis

Benefits to Fitness, Symptoms, Hippocampal Volumes, and Functional Connectivity

Katherine S. F. Damme; Tina Gupta; Ivanka Ristanovic; David Kimhy; Angela D. Bryan; Vijay A. Mittal


Schizophr Bull. 2022;48(6):1394-1405. 

In This Article

Abstract and Introduction


Background and Hypothesis: Individuals at clinical high risk for psychosis (CHR-p) are less fit than nonclinical peers and show hippocampal abnormalities that relate to clinical symptoms. Exercise generates hippocampal neurogenesis that may ameliorate these hippocampal abnormalities and related cognitive/clinical symptoms. This study examines the impact of exercise on deficits in fitness, cognitive deficits, attenuated psychotic symptoms, hippocampal volumes, and hippocampal connectivity in individuals at CHR-p.

Study Design: In a randomized controlled trial, 32 individuals at CHR-p participated in either an exercise (n = 17) or waitlist (no exercise) (n = 15) condition. All participants were sedentary at use and absent of current antipsychotic medication, psychosis diagnoses, or a substance use disorder. The participants completed a series of fitness, cognitive tasks, clinical assessments, and an MRI session preintervention and postintervention. The exercise intervention included a high-intensity interval exercise (80% of VO2max) with 1-minute high-intensity intervals (95% of VO2max) every 10 minutes) protocol twice a week over 3 months.

Study Results: The exercise intervention was well tolerated (83.78% retention; 81.25% completion). The exercising CHR-p group showed that improved fitness (pre/post-d = 0.53), increased in cognitive performance (pre/post-d = 0.49), decrease in positive symptoms (pre/post-d = 1.12) compared with the waitlist group. Exercising individuals showed stable hippocampal volumes; waitlist CHR-p individuals showed 3.57% decreased hippocampal subfield volume. Exercising individuals showed that increased exercise-related hippocampal connectivity compared to the waitlist individuals.

Conclusions: The exercise intervention had excellent adherence, and there were clear signs of mechanism engagement. Taken together, evidence suggests that high-intensity exercise can be a beneficial therapeutic tool in the psychosis risk period.


Exercise may be a promising intervention for individuals across many stages of psychosis, including those at clinical high risk for psychosis (CHR-p).[1–9] Psychosis is associated with poor physical health,[1,6,10–12] which extends to those at CHR-p who are less active,[13] less fit,[14] and experience more barriers to exercise.[10,15–19] Moderate to intense aerobic exercise engages neurogenesis and the production of brain-derived neurotrophic factors for the maintenance of healthy neurons in the hippocampus.[1–9] This mechanism may be particularly impactful in CHR-p populations who have decreased hippocampal volumes[20–22] and abnormal shape.[23] These hippocampal abnormalities also may relate to clinical symptoms, cognitive symptoms, and severity in course of psychosis.[24] Moderate to intense aerobic exercise interventions may combat these disease-driven hippocampal pathophysiology.[4,13,20,25–27]

Increased neurogenesis and plasticity[2,25,26] in the hippocampus after exercise[24] may address a broad range of hippocampal-mediated behaviors impacted in psychopathology[23,25,28] In formal psychosis, hippocampal pathology has been well documented[7,16,20,23,29–31] Pajonk et al showed that aerobic exercise increased hippocampal volume by 14% in schizophrenia patients and that this volume increase was proportional to the improvement in cardiovascular fitness (ie, VO2max), hippocampal-dependent cognition (ie, working memory), and total psychosis symptoms.[28] Despite this evidence,[28] meta-analyses of exercise interventions in psychosis[32] show that there is frequently no increase in hippocampal volume in the exercise intervention group. Instead, these studies find a stable hippocampal volume in the exercise group and significant decreases in volume within the no exercise group.[8,26,33] The latter suggests that exercise intervention may prevent pathogenic decreases in hippocampal volumes,[28,32] and may be an effective early intervention for individuals with or at high-risk for psychosis.

The promise that exercise interventions show in psychosis disorders[4,6,32] extends to individuals at CHR-p.[7] Notably, even those individuals at CHR-p that do not convert to psychosis show elevated risk for poor physical and mental health outcomes (eg, lower cardiovascular fitness,[14] depression,[34,35] anxiety,[35,36] sleep disturbance),[37–39] all of which may benefit from exercise intervention. Beyond these broad benefits individuals at CHR-p have decreased aerobic fitness,[14] decreased hippocampal volume,[20,23] and related cognitive deficits such as episodic memory dysfunction, specific mechanisms that are directly engaged addressed by exercise intervention.[40–42] Mittal et al found that objectively assessed greater physical activity (ie, actigraphy) was related to larger gray matter volume and better occupational function in individuals at CHR-p at a single timepoint.[13] With few exceptions,[7,13,14] much of this research relies on retrospective, self-reported evaluations of fitness, which are often biased or inaccurate,[14] and studies rarely manipulate fitness or activity level as an intervention in a lab setting.[7] Indeed, randomized controlled trials have focused on psychosocial, pharmaceutical, or combined (ie, psychosocial with pharmaceutical) interventions for individuals at CHR-p.[43] Despite recent initiatives greatly expanding comprehensive care for individuals in early psychosis,[44] these programs are not widely available, are resource demanding, and experience problems with treatment engagement.[45] Although there is some evidence that certain psychosocial and pharmaceutical treatments may reduce or delay conversion to psychosis,[46] they do not improve cognition or negative symptoms.[47,48] In contrast, exercise has shown benefits to both cognition and negative symptoms and could be a beneficial treatment target.[2,5,49]

In a supervised, open-label exercise intervention by Dean et al, CHR-p individuals who participated in aerobic exercise showed reduced positive symptoms and improvements in both hippocampal-occipital connectivity and cognitive function.[7] In this study, individuals were assigned to exercise on a treadmill either twice a week or 3 times a week. Despite many areas of improvement (symptoms, cognition, hippocampal-occipital connectivity), there was no improvement in fitness (ie, VO2max). This study demonstrated the tolerability, feasibility, and benefits of exercise for individuals at CHR-p. However, this study lacked a waitlist control group for comparison. This methodological approach is not able to account for symptom remission, which is particularly important in CHR-p populations that experience an estimated 43%[50]–59%[51] remission within a 12-month period. It is thus critical to examine the impact of exercise intervention in a randomized controlled trial.

The current study is the first randomized controlled trial to examine the potential benefits of exercise interventions for individuals at CHR-p in terms of cardiovascular fitness (VO2max), hippocampal-dependent episodic memory, attenuated psychosis symptoms, and hippocampal subfield volumes. This study extends findings from an open-label, phase one study[13,16] that demonstrated the potential benefits and feasibility of exercise interventions within a CHR-p group. First, this study reports important features of retention and feasibility in the methodological approach and the efficacy of the exercise intervention in improving fitness. Next, analyses investigate the impact of the exercise intervention on hippocampal-dependent episodic memory and attenuated psychotic symptoms with the expectation that treatment will improve cognitive and clinical symptoms. Then, randomized groups were compared in terms of hippocampal subfields volume changes (potential benefits of exercise and risk-related processes in the waitlist group) with the expectation that exercise will increase hippocampal volume. Finally, hippocampal-occipital connectivity was compared across groups over time to replicate and extend the open-label exercise study that observed increased exercise was associated with increased hippocampal-occipital connectivity.[7]