Therapeutic Potential of Physical Exercise in Early Psychosis

Onset of psychosis is believed to be associated with neuronal dysregulation and degeneration. Reductions in brain volumes have been related in part to neuronal loss but more substantially to loss of neuronal connectivity, loss of dendritic spines, and reductions in supporting glial cells. These changes have been associated with alterations in neurotrophic factors in the brain. Recent evidence suggests that aggressive synaptic pruning may underlie onset of psychosis for some individuals (1). While reductions in regional brain volumes have been demonstrated in individuals in their first episode of schizophrenia, further deterioration has been shown to occur even after initiation of treatment (2, 3). The disruption of myelination has been proposed as one mechanism underlying these effects (4, 5). Duration of untreated psychosis is associated with both symptom severity and poor functional outcomes (6). Therefore, the time around onset of psychosis is considered a critical period when neuronal systems in the brain are vulnerable to deterioration, fragile, unstable, and in need of protection and, possibly, regeneration.

Several neuroprotective strategies have been attempted for people experiencing early stages of psychosis. One study demonstrated that for individuals at clinical high risk, omega-3 fatty acids appeared to reduce the risk of developing schizophreniform disorder (7, 8). However, results from other omega-3 trials for prevention and treatment of schizophrenia have not demonstrated consistent results (9). N-acetylcysteine supplementation as an adjuvant to antipsychotics has demonstrated reductions in total and negative symptoms in patients with schizophrenia, possibly because of its ability to reduce oxidative neuronal damage (10, 11).

Antipsychotic medication has been postulated to be neuroprotective regarding myelination and through modulation of brain-derived neurotrophic factor (BDNF). Antipsychotic treatment is associated with improvement in psychosis and completion of myelination if used consistently (4). Interestingly, it has been hypothesized that medications that target remyelination, such as those used for multiple sclerosis, may have certain advantages over antipsychotics in patients with schizophrenia (5). Another mechanism thought to add neuroprotection by antipsychotic treatment is through up-regulation of BDNF. However, the BDNF-inducing effects that antipsychotics potentiate appear to decrease over time (12), and there is some evidence of longitudinal gray matter volume changes (13). Antipsychotic treatment has also been associated with cardiometabolic dysregulation, overriding the genetic linkage between schizophrenia and anthropomorphic markers of thinness (14). People in early psychosis are particularly sensitive to these effects and may benefit from using exercise to maintain physical fitness and prevent weight gain and insulin, glucose, and lipid dysregulation (15, 16).

Neuroplastic and Neurogenic Effects of Physical Exercise

It is remarkable that exercise affects the same neuroprotective factors that are thought to be targeted by neutraceutical and antipsychotic medications. Exercise decreases neuroinflammation, up-regulates neurotrophic growth factors, potentiates remyelination, and appears to protect against age-related cognitive decline (17). It was first noticed in cohort studies that sedentary adults developed significantly more cognitive impairment and dementia than physically active adults (18).

It was later found that exercise increases systemic BDNF, which freely passes through the blood-brain barrier into the CNS, where it stimulates neurogenesis and synaptic plasticity (19). In landmark MRI studies evaluating the effects of exercise on the human brain, Colcombe and colleagues (20) discovered significant increases in white and gray matter tracts, thereby demonstrating that exercise can increase myelination and neurogenesis. A follow-up study by Erickson and colleagues (21) demonstrated that aerobic exercise could reverse the physical damage of age-related cognitive decline and increase hippocampal volume. Additional studies have since demonstrated that the territories of the brain that are most protected and regenerated by exercise are the frontal and hippocampal-temporal regions, which are centers of executive function, memory, and cognition (19) and are specific targets for neuroprotection in schizophrenia.

Firth and colleagues (22) examined 10 trials (total N=385) that specifically tested the impact of exercise on cognitive function in patients with schizophrenia. Exercise significantly improved global cognition, working memory, social cognition, and attention/vigilance. However, there were nonsignificant changes in processing speed, verbal and visual memory, and reasoning and problem solving. Subgroup analysis suggested that higher doses of exercise led to larger improvements.

Firth and colleagues further investigated trials that included evaluations of the mechanisms that exercise affects in patients with schizophrenia (23). Through examining imaging studies, Firth et al. found that exercise significantly improved brain volume in all but one small study, which was consistent with the effects of exercise found in other populations (21, 24). Through analysis of systemic biomarkers that correlate with neuroprotection and regeneration, four of five studies that examined serum BDNF found increases related to exercise, although significance was limited to two studies because of small samples in the other two (N=13 and N=4).

Despite the potential physical and mental health benefits of exercise, people with schizophrenia generally engage in very low levels of physical activity and have high levels of sedentary behavior, which has been associated with poorer cognitive performance (25–27).

Physical Exercise in Early Psychosis

There is limited evidence on the impact of exercise in the prodromal and early phases of schizophrenia. In a study of ultra high-risk youths, Mittal and colleagues (28) demonstrated a significant association between meeting ultra high-risk criteria and having a sedentary lifestyle or engaging in markedly less light and vigorous activity, and an association that fell short of significance for those engaging in less moderate activity. The youths also had significantly smaller hippocampal volumes and right parahippocampal volume than matched control subjects. McEwen and colleagues (29) demonstrated that low compared with high physical activity levels were associated with significantly smaller volumes of total, prefrontal cortical, and hippocampal gray matter as well as of cortical thickness in the dorsolateral and orbitofrontal prefrontal cortex in 14 patients with first-episode schizophrenia. Sormunen and colleagues published findings (30) from the Cardiovascular Risk of Young Finns cohort study (N=3,596) demonstrating that inactivity was a strong independent risk factor for the development of schizophrenia. In a dose-dependent response, the lowest compared with the highest physical activity level was associated with a 3.87-fold higher risk of developing schizophrenia. Lack of participation in competitive sports, which provides both social support and physical activity, was associated with a 4.88-fold higher risk of developing schizophrenia.

Nuechterlein and colleagues (31) tested aerobic exercise plus cognitive training compared with cognitive training alone for a 10-week period for people in their first episode of schizophrenia. Their study design was inspired by animal models showing that combining aerobic exercise with learning tasks generated up to 30% more neurons than either intervention alone (32). Although this matched feasibility trial was too small to show significance (N=16), a large effect size was noted in social cognition, working memory, speed of processing, and attention/vigilance for the physical exercise group. Benefits were also observed for independent living, family network relationships, and working productivity, although these did not reach statistical significance.

Firth and colleagues also examined the benefits of 10 weeks of individualized exercise training for 38 patients with first-episode psychosis (33). This nonrandomized feasibility study found significantly greater improvement in the exercise group for total psychiatric symptoms (as measured by the Positive and Negative Syndrome Scale), negative symptoms, psychosocial functioning, and verbal short-term memory. Furthermore, a qualitative study of the same sample investigated how patients themselves subjectively experienced the exercise sessions (34). The findings support those of our own case study, with the majority of participants reporting acute mental health benefits during and immediately after engaging in moderate to vigorous physical activity.

Mittal and colleagues (35) conducted an exercise feasibility trial for sedentary youths at ultra high risk for developing schizophrenia. Nine of 12 recruited participants completed the 12-week trial with moderate to vigorous exercise 2 to 3 days per week. There were medium to large effect sizes for decreasing positive symptoms, small to medium effect sizes for decreasing negative symptoms, and improvements in social and role functioning and cognition. These changes were matched by increasing connectivity between the left hippocampus and the left and right occipital cortices. However, no change in hippocampal volume was noted. Mittal and colleagues are currently reexamining these results in a phase 2 clinical trial.

Lastly, McEwen and colleagues (36) conducted a randomized controlled trial in 37 patients with early schizophrenia. Patients were randomly assigned to either cognitive training alone or cognitive training plus aerobic exercise for 6 months. Cortical thickness significantly improved in the exercise group and was associated with improved reasoning, problem solving, global social functioning, global role functioning, verbal learning, and working memory. Cortical thickness decreased in the cognitive-training-alone group during the same period.

Behavioral Change Strategies

While approaches to assisting people with psychotic disorders with initiating and maintaining active physical exercise vary across studies and have not been directly compared, the following approach represents a composite of commonly used techniques, adapted to the clinical practice setting.

The first step is to carefully assess exercise participation, both lifetime and current, as part of initial evaluation (Figure 1). This communicates the importance of prioritizing physical exercise in medical care while also providing a basis for making exercise recommendations. After an assessment of the presenting problem and the contribution of the patient’s lifestyle, educate the patient about the role of physical exercise as a treatment option for his or her disorder. Inquire what types of exercise the patient prefers, as engaging in a type of exercise that the individual finds enjoyable will be the most likely to be sustainable over the long term. It is also important that the type of exercise be accessible (for example, if the patient enjoys swimming, confirm access to a pool; if the patient likes to bike outdoors, check whether or not he or she has access to a bicycle and safe places to ride). If patients do not have experience or preferences with regard to exercise, try to assist them in finding suitable options that are available to them. It is also important to consider safety when recommending an exercise program.

As the treatment plan is developed with the patient, make clear recommendations if the patient chooses to include an exercise intervention in his or her plan. These recommendations should consider the patient’s current physical and mental capacity as well as target goals for treatment of his or her disorder based on the available evidence. Be specific about the type, duration, frequency, and intensity of the exercise that is ultimately recommended (Figure 1). Help the patient map out a weekly exercise schedule and set realistic goals. A good approach to helping the patient set goals can be framed using the acronym SMART—specific, measurable, attainable, realistic, and timely. Encourage the patient to use a behavioral monitoring tool, such as a training log or a wearable device, and to track health parameters such as weight, diet, medication adherence, sleep, and mood in the same log. Assess the patient’s adherence to the exercise plan at each follow-up visit, similar to assessing adherence to other treatment modalities (Figure 1). If the patient has not adhered to the plan, consider barriers and assist the patient in refining the plan to achieve greater success (37). Motivational supports such as exercising in a group or class, establishing an exercise partner such as a friend or family member, training for an exercise event, and recommended readings or videos may assist patients who are struggling to achieve adherence to their exercise plan. For patients who are resistant to inclusion of exercise in their care regimen, motivational interviewing techniques may help the patient consider behavior change related to increased activity (38).

During the monitoring process, it is important to highlight any success the patient has had with engaging in exercise. Engaging the patient in assessing outcomes of exercise may support long-term change. Carefully assess the patient’s experience during and after the exercise activity (39). Help the patient and family recognize how exercise may have changed the way the patient felt (better mood and energy, clearer thinking, enhanced self-esteem, improved body image, etc.) and how long it lasted (34). This will support growing connections between exercising and feeling better that can motivate further activity (37). At the end of the review, develop a shared decision for exercise goals for the coming interval to be reviewed at the next session. Always give generous recognition for the success the individual has achieved and assist him or her in viewing it as a process of growth. This iterative process of medical recommendation, close monitoring, and reinforcement of success was highly effective in supporting our patient in attaining a high level of regular physical exercise. Several studies also identify better adherence and improved outcomes when a trained fitness professional is incorporated to deliver the fitness intervention, which our patient also found valuable (40).

Conclusions

Individuals with psychotic disorders may benefit from establishing an exercise regimen as part of their care. Exercise effects neuroprotective mechanisms, such as decreasing inflammation, increasing neurogenesis and neuroplasticity, and remyelination of white matter tracts, resulting in at least a partial reversal of the regional brain matter loss that is seen in patients with psychosis. Clinically, there is substantial evidence that physical exercise can result in improvements in cognition, mood, and positive and negative symptoms. Further research is needed to assess optimal dose and type of exercise, motivational strategies, and potential impact on self-efficacy, reward, and social engagement. Initial evidence suggests that exercise may also have promise in early psychosis. It remains unknown whether exercise, in combination with other evidence-based interventions, might reduce the rate of conversion from attenuated psychosis syndrome or schizophreniform disorder to schizophrenia.

Remission from early psychosis in the context of evidence-based coordinated specialty care is not entirely unexpected, independent of exercise. However, the patient described in our case rapidly achieved high levels of physical exercise in response to specific lifestyle recommendations and a behavioral reinforcement process in our early psychosis program that may have contributed to his good outcome. While serial imaging and serum BDNF levels were not available for our patient, he did identify improvements in motivation, mood, and cognitive function and a return to his previous level of social and academic functioning in response to treatment that incorporated regular physical exercise. This is the first report of remission of psychosis that we are aware of in which vigorous physical exercise may have been a factor, and it is not the only such case we have seen.

Whether for the purpose of improving general health or the possibility of improving clinical symptoms, it would be beneficial for health care providers to assess physical activity and educate patients about exercise as a treatment option. Integrating exercise as a core component of early psychosis treatment for those who wish to undertake it has a range of potential benefits for mental and physical health, including potential synergies with other treatment components (41). Coordinated specialty care teams might incorporate a fitness instructor or link with a local fitness program to facilitate physical exercise, as implemented by the “In SHAPE” program (40, 42). It is important to make specific recommendations for exercise and support and monitor adherence when patients choose exercise as part of their care. Knowledge of the evidence supporting the efficacy of exercise in psychiatric disorders and the principles of behavioral change outlined here will help clinicians to be effective in the use of exercise in clinical care.