Effect of Exercise on Major Depressive Disorder and Schizophrenia: A BDNF Focused Approach

Abstract

Psychiatric disorders are remarkable health problems that cause a massive social and economic burden, and the issue of their long-term and effective treatment is subjected to discussion. The effect of physical activity and exercise is under investigation in the treatment of the major depressive disorder (MDD) and schizophrenia which are accompanied by cognitive dysfunctions. Scientists focus on the positive effects of exercise on learning, memory and attention parameters while investigating the regulatory role of brain-derived neurotrophic factor (BDNF). In this review, the effect of aerobic exercise on peripheral BDNF levels in MDD and schizophrenia is examined by including human studies in which acute and chronic aerobic exercise are applied. The results showed that aerobic exercise caused different responses on BDNF levels, and some of the studies were accompanied by the improvement in cognitive functions in BDNF changes. In order to comprehend the effect of aerobic exercise in MDD and schizophrenia, it is understood that applying studies on larger and paired participant groups with different exercise frequencies and tensions in necessary.

INTRODUCTION

Epidemiological studies indicate that physical activity and exercise can prevent and delay the initiation and development of psychiatric disorders and have therapeutic effects when used as supportive therapy. Numerous animal models and human studies have shown that exercise promotes psychological health and well-being, increases cognitive performance and functional recovery, and provides a series of structural changes in the brain (1, 2). Due to its roles in learning and memory, this research focuses on the hippocampus and also emphasizes the mechanisms of plasticity triggered by exercise in the prefrontal cortex where executive functions are embedded (3). It is considered that the mediators in the relationship between exercise and the brain may be myokines secreted by muscles that act as a secretory organ in the periphery, as well as a series of growth factors. Brain-derived neurotrophic factor (BDNF), a member of the family of neurotrophic factors involved in neuronal transport, modulation, and plasticity, has become the focus of research seeking an understanding of the relationship between exercise and the brain.

BDNF

BDNF, secreted from both the central nervous system and peripheral tissues, is a protein of the neurotrophin family, including the nerve growth factor, neurotrophin-3 and neurotrophin-4/5. This structure, which is synthesized in the form of pre-pro-BDNF in the endoplasmic reticulum and which moves to the trans-golgi network through the Golgi body, is secreted as mature BDNF or pro-BDNF and is stored in platelets at a high level (4). BDNF, with the sources of neurons, microglia and astrocytes in the brain, are also secreted from vascular endothelium, lymphocytes and smooth/striated muscles. Tropomyosin receptor kinase B (TrkB), one of the BDNF receptors, binds to the mature BDNF while p75 (low-affinity nerve growth factor receptor) binds to pro-BDNF.

BDNF was first isolated from the tissue of pig brains in 1982 and detected in human blood in 1995. It has been reported to cross the blood-brain barrier and the serum and plasma levels of BDNF have been associated with age, gender, and body mass index (5). BDNF is a protein that affects neuronal survival, neurogenesis and neuroplasticity in the central nervous system and play a role in cell differentiation, axon and dendrite growth, synapse formation and synaptic plasticity, and its expression and release are related to neuronal activity. BDNF is critical for synaptic formation in dopaminergic, glutamatergic and serotonergic neuronal conduction and cognitive processes. The main effect of BDNF is on synaptic function and neuronal morphology in a region-specific manner (6). It is responsible for short-term memory and long-term memory potentiation and performs tasks related to remembering, cognition, emotional state, spatial direction, and learning (7). BDNF messenger RNA (mRNA) has been widely observed in the hippocampus and cerebral cortex. BDNF-containing vesicles are found in both the axonal terminals and dendrites, and BDNF is also secreted from astrocytes (8). BDNF secretion may be via Ca²⁺ influx from the postsynaptic or presynaptic area Ca²⁺ influx or Ca²⁺ release from intracellular stores (9). Studies reporting the cognitive benefits of exercise suggest that BDNF is involved in this mechanism (10, 11). Animal studies showed that BDNF and tropomyosin receptor kinase B (TrkB) receptor activation was increased in various brain regions during and after exercise, while human studies detected peripheral BDNF in the serum and plasma and found a relationship between the cerebral and peripheral BDNF levels, which varied according to the type, duration and frequency of exercise in different studies (12–14).

Exercise, BDNF and Cognition

Meta-analytical reviews indicate that acute and chronic aerobic exercise has a developmental effect on cognition with the most dramatic effect seen on its executive functions (15). In this area, where the mechanism of action is not fully elucidated, BDNF is suggested to have a potential mechanism. The BDNF response to aerobic exercise has been investigated in the literature in relation to different acute and chronic exercise programs at different doses. In addition to aerobic exercise-induced BDNF responses, these studies have also examined cognitive performance findings. The method generally used in the studies examining the effects of aerobic exercise on BDNF and cognition is the measurement of the BDNF level before and after exercise and the application of cognitive tests. The effect of BDNF on cognition has been explored mainly through memory tasks. The definition of the hippocampus as the main site for BDNF expression in the brain (16) its effect on memory tasks makes this choice meaningful. Although human studies offer limited opportunities to monitor BDNF levels in the brain, it has been found that the peripheral BDNF levels, hippocampal volume, and spatial memory results are correlated (17).

Effect of Exercise on BDNF and Cognitive Function in Healthy Individuals

Meta-analytical reviews examining the effect of acute exercise on peripheral BDNF (18) reported contradictory results, but predominantly indicated an increase in BDNF and agreed that this increase was transient. On the other hand, due to the different methods used in these studies, it is established that the responses detected were not completely consistent. After 30 minutes of acute exercise, an increase was observed in the cognitive functions and BDNF levels of healthy subjects evaluated by the Face Recognition Test and the Stroop Test, but the relationship between the two parameters was not evaluated (19).

In a review suggesting a positive relationship between exercise severity and peripheral BDNF levels, it was reported that high-intensity acute exercise provided the greatest increase in BDNF in healthy subjects. On the other hand, the BDNF level returned to baseline between 10 and 60 minutes (18). After 20 minutes of intense exercise, healthy individuals showed improvement in cognitive findings and BDNF levels assessed by the visual spatial perception test, and a significant relationship was found between motor memory and BDNF data (20).

In a study evaluating cognitive performance by the reaction time in the Visual Spatial Attention Test and EEG after 30 minutes of moderate acute exercise in non-trained individuals, the BDNF levels increased and the reaction time decreased in exercise groups. The neuroelectric signals, which were interpreted as increased attention in EEG (P3 amplitude) and readiness to respond to stimulus (CNV amplitude), were only increased in trained individuals. A significant relationship between BDNF and cognitive performance levels was not found. The researchers interpreted their results as cardiovascular fitness being involved in the mechanism of action of exercise on cognition (21).

A study conducted with healthy subjects that performed severe acute aerobic exercise evaluated the BDNF level, inhibitory control using the Stroop Test, and cognitive flexibility using Part B of the Trail-Making Test, and reported increased cognitive success findings and BDNF levels. A significant relationship was found between the increased BDNF level and cognitive flexibility success findings. The authors suggested that improvement in cognitive performance related to the prefrontal area in response to acute exercise could be attributed to an increase in the BDNF level (10).

In another study conducted in healthy individuals, the BDNF level and executive functions were evaluated using the Wisconsin Card Sorting Test before and after high-intensity intermittent exercise, and while the plasma BDNF level did not change, the serum BDNF level increased. According to the results of the Wisconsin Card Sorting Test, the number of categories completed and the number of correct responses increased, and the number of total and recurrent errors decreased. The authors did not find a significant relationship between BDNF concentration and the results of executive functions related to the prefrontal cortex; however, they commented that cognitive performance responded more to the increased intensity of exercise (22). It was also reported that the increase in BDNF after acute aerobic exercise was associated with exercise duration. The increase in BDNF was significantly higher than in exercise lasting longer than 30 minutes compared to exercise for less than 30 minutes. This can be interpreted as different exercise times affecting brain functions differently. In a study on acute exercise and its effect on cognitive functions, it was shown that cognitive benefit emerged only through exercise lasting longer than 20 minutes (23). Other studies suggested that the duration and intensity of exercise produced the best result related to moderate exercise, and therefore the effect of regular exercise on BDNF and cognition was more dramatic (18, 24). Regular exercise increases the BDNF level in the hippocampus and improves learning and memory processes.

Chronic exercise in children and young adults improved working memory, selective attention, and inhibitory control findings (25). In a six-month aerobic exercise study conducted with elderly men, the gray matter volume increased and the peripheral BDNF increased in the prefrontal and cingulate cortex areas associated with increased physical activity (26).

Effect of Exercise on BDNF and Cognitive Function in Major Depressive Disorder (MDD) and Schizophrenia

MDD, which is one of the leading causes of global disease burden, manifests with cognitive and somatic symptoms. In recent years, BDNF has been used as a biomarker in psychiatric disorders, such as MDD, schizophrenia and bipolar disorder, and the BDNF level has been shown to be lower in patient groups than in healthy individuals (27–29). It was suggested that the BDNF level is lower in MDD cases, and a higher level BDNF is associated with less depressive symptoms and improved cognitive functions compared to the healthy population (30, 31). In case studies, granular neuron loss, reduced hippocampal volume, and regressed peripheral level of BDNF and BDNF mRNA expression in lymphocytes were reported (32), and suicidal behavior was associated with a low peripheral/cerebral BDNF level (in the hippocampus and prefrontal cortex) (33). It was found that the peripheral level of BDNF could be used to predict the response to antidepressant treatment in MDD, and there was an increase in this level in response to drug therapy; however, the results regarding the relationship between improvement in mood and BDNF increase were contradictory (34).

It is not yet clear whether the clinical manifestation of the BDNF variant Val66Met is a risk factor for MDD. However, in a review, it was proposed that this variant reduced the response to drug treatment (35). Schizophrenia, on the other hand, is a severe mental disorder characterized by psychosis and generally presents with cognitive dysfunctions related to problem solving, memory, and executive functions (36). Animal models have drawn attention to the role of BDNF in the development and activation of psychosis-related neurotransmitters. It is stated that the changes in the BDNF level may contribute to neuroplasticity disorder during brain development and synaptic connection disorders, and the morphological, neurochemical and cell architecture anomalies observed in the brain in schizophrenia (37). It is well known that in schizophrenia, neurocognitive losses are observed in memory, attention, processing speed, and executive functions. A meta-analytical review of 16 studies reported that patients with schizophrenia had significantly lower peripheral BDNF (27), with memory disturbances and smaller hippocampal volume findings being associated with a reduced BDNF level (38). In untreated psychosis, the serum BDNF level was shown to be low and correlated with the duration of psychosis, and drug-induced psychosis models indicated a relationship between a reduced BDNF mRNA concentration and psychotic symptoms (39). The visual spatial memory performance and attention were found to be poor in schizophrenia patients with the BDNF Val66Met variant, and a low BDNF level was observed to be correlated with reduced cognitive functions (40).

MATERIAL AND METHODS

For this review, human studies published in English were cross-searched on the PubMed and Web of Science search engines using the keywords BDNF-exercise-cognition-major depressive disorder/schizophrenia and BDNF-exercise-major depressive disorder/schizophrenia and those that only included aerobic exercise were selected. Two studies examined the effect of aerobic exercise on cognition and BDNF in schizophrenia, three examined the effect of aerobic exercise on cognition and BDNF in MDD, and seven studies examined the effect of aerobic exercise on BDNF in MDD. Three of the studies used acute and nine used chronic aerobic exercise as a method. The total number of participants in 12 studies was 385. In MDD and schizophrenia, the responses of peripheral BDNF to exercise, the relationship between exercise and cognitive performance findings, and the underlying mechanism of these responses were discussed, and how BDNF and cognitive functions changed with aerobic exercise was examined.

RESULTS

The findings suggest that aerobic exercise increases the peripheral BDNF level. No significant increase in BDNF was observed in three of the MDD studies, whereas a significant increase in BDNF was noted in all the remaining studies. While four studies examining BDNF and cognitive performance findings together showed a significant increase in both parameters, the improvement in cognitive performance was not accompanied by an increase in BDNF in one of the studies.

DISCUSSION

Effects of Exercise in MDD

It is reported that 5% of the global population has been diagnosed with MDD and 1% with schizophrenia, and 20-30% of all of these patients are resistant to treatment (41– 43). It is known that in MDD, the workload capacity of individuals is reduced by 80 to 90% compared to their healthy counterparts, and physical activity is decreased in schizophrenia and is accompanied by cognitive disorders (44, 45).

Studies have shown that neuronal activity affects the synthesis, secretion and signaling of neurotrophin, which has an impact on the postsynaptic response, synaptic morphology, presynaptic transmitter secretion, and membrane excitability.

In nine of the 12 studies we reviewed, an increase in BDNF was reported in the period following aerobic exercise (46–54). These data seem to agree with the premise that exercise contributes to the promotion and maintenance of neuron functions through a mechanism mediated by neurotrophins. It has been suggested that one of the mechanisms responsible for increased BDNF may be the increase in the cerebral blood flow. Another proposition is that exercise-related increase in the insulin-like growth factor (IGF)-1 and norepinephrine levels may increase the expression of BDNF mRNA. It has also been argued that decreased blood volume due to water loss may increase the BDNF concentration.

Table 1.

Summary of studies investigating the effect of aerobic exercise on BDNF and cognitive functions in schizophrenia and major depressive disorder.

Researcher	Participants (Exercise/Control)	Exercise modelity	Cognitive effect	BDNF response
Kimhy et al., 2015*	13/13	12 weeks, 3 times per week, 60 minutes	In exercise group global cognitive performance↑	In exercise group %11, in standard treatment group %1,9 ↑
Nuechterlein et al., 2016*	7/9	10 weeks, 4 times per week, 30-45 minutes	In exercise group social cognition, working memory, processing speed, attention-vigilance performance ↑	In exercise group ↑
Gourgouvellis et al., 2018 **	8/8	8 weeks, 3 times per week, 60 minutes	In exercise group global cognition, recognition memory, visual learning and memory performance ↑	In exercise group ↑
Vedovelli, 2017**	22/10	12 weeks, 3 times per week, 60 minutes	In exercise group processing speed, executive function, attention, working memory, işlemleme hızı, recall, response inhibiton ↑	In exercise group ↑
Krogh et al., 2014**	41/38	12 weeks, 3 times per week, 45 minutes/streching	In aerobic exercise group verbal memory performance ↑	No significant change
Kallies et al., 2018**	30/-	Acute aerobic exercise, not specified frequency/duration	-	↑
Kerling et al., 2017 **	22/-	6 weeks, 3 times per week, 45 minutes	-	No significant change
Salehi et al., 2016**	20/-	4 weeks, 3 times per week, 40-45 minutes	-	↑
Schuch et al., 2014**	15/11	3 weeks, 3 times per week, not specified duration	-	In exercise group ↑
Toups et al., 2011**	70/-	12 weeks, not specified frequency	-	No significant change
Meyer et al., 2016**	24/-	Acute aerobic exercise, 30 minutes	-	↑
Meyer et al., 2016**	24/-	Acute aerobic exercise, 30 minutes	-	↑

^*Schizophrenia studies

^**MDD studies

BDNF plays several important roles in synaptic plasticity and affects different aspects of synaptic transmission. In the central nervous system, BDNF can increase the number of excitatory and inhibitory synapses by regulating axonal morphology or directly improving synapse formation (6). Furthermore, it enhances the maturation and stabilization of neurotransmitter secretion at the cellular and molecular level, which increases the number of functional synapses. It regulates the increase in proteins involved in neurogenesis, learning and memory, and neuronal survival, including those regulating the protein quality control, mitochondrial biogenesis, and the resistance of cells to oxidative, metabolic and proteotoxic stress. In the literature, it has been reported that BDNF secreted from the cerebral endothelium following acute aerobic exercise was responsible for the effect of exercise on cognition (55). This function of BDNF appears to be consistent with the memory responses obtained from studies that included the findings of cognitive function in this review.

The mechanism of action of BDNF on neuroplasticity is claimed to be through increasing the calcium mRNA, cAMP response binding protein (CREB), and synapse I level (56). Exercise can produce persistent increases in phosphorylated CREB and BDNF levels that continue throughout the exercise period. An exercise-induced increase in BDNF levels increases the expression of key presynaptic molecules associated with synaptic transmission, such as synapse I and synaptophysin with a vesicular function at the presynaptic nerve terminals. Especially in glutamatergic synapses, BDNF plays a key role in initiating signal transduction with the TrkB and p75 receptors in regulating activity-dependent synaptic structure and function. Mature BDNF primarily stimulates the TrkB receptor, while proBDNF targets the p75 receptor. Mature BDNF binds to the extracellular domain of receptor TrkB and activates phosphorylated TrkB, phosphotidylinositol-3 kinase (PI3K), mitogen-activated protein kinase (MAPK), phospholipase-Cγ (PLCγ) and guanosine triphosphate (GTPase) pathways. The PI3K pathway showing an antiapoptotic effect modulates the synaptic plasticity of N-methyl-D-aspartate (NMDA) receptors and increases dendritic growth and branching (Figure 1) (57).

Figure 1.

Binding of mature BDNF to receptor TrkB activates PI3K, MAPK, PLCγ and GTP-less pathways.

The PLCγ pathway is responsible for increased CaMKII and CREB activation through the secretion of intracellular Ca2+. The MAPK signal is required for the activation of the extracellular signal-regulated kinase 1 and CREB. This pathway is important for the synthesis of the cytoskeleton protein, as well as dendritic growth and branching in hippocampal neurons. The activation of the GTPase pathway stimulates the synthesis of actin and microtubules, resulting in the growth of neuronal fibers (58). The BDNF responses seen in the reviewed studies on chronic aerobic exercise may be related to increased CREB phosphorylation of the repetitive stimulus, leading to prolonged structural and functional changes in synapses. It is reported that the CREB function in activity-dependent long-term neuronal plasticity is a necessary molecule for long-term memory formation. It has been reported that by increasing the presence and activity of CaMKII and BDNF levels and reducing calcineurin phosphatase levels, exercise boosts the synthesis of important signaling molecules that are critical for learning and memory (59).

In their study with MDD cases, Gourgouvellis et al. observed an increase in the BDNF level and visual learning, memory and recognition memory performance following cognitive behavioral therapy and aerobic exercise (48). In accordance with these results, in the literature, increased BDNF and CREB mRNA levels were associated with exercise in mice, and the highest BDNF expression was associated with the highest CREB expression and spatial memory ability (60). In another study, it was found that exercise increased the active CREB form, and the learning ability of mice was also significantly increased after exercise, and the highest elevation in the BDNF level belonged to those that learned fastest (61).

The acute aerobic exercise studies included in this review (53, 54) also reported elevated BDNF levels. Considering the studies that did not report an increase in BDNF in response to chronic aerobic exercise, it can be regarded that transient BDNF elevations are responsible for the chronic benefits of exercise in MDD. It could be the case that exercise has a curative effect through transient elevations in BDNF without long-term changes in basal BDNF, which leads to long-term neurophysiological changes. The clinical effectiveness of exercise in curing MDD may also result from its favorable effects on monoaminergic function, neurogenesis, and immunity. Exercise causes changes in markers associated with the monoamine metabolism, including monoamine, monoamine receptors, and carriers, and among these changes are the activation of serotonergic neurons in the dorsal raphe nucleus (DRN) by low-intensity exercise. It has been suggested that the effect of exercise on serotonergic activity can explain its curative effect on depressive symptoms. The central serotonergic system is built into the DRN and has projections over large areas of the brain. It is considered that exercise demonstrates its antidepressant effect through the serotonergic neurons in DRN. Accordingly, increased serotonin synthesis, metabolism, and secretion are observed during and after exercise. It has been shown that exercise has the effects of inducing hippocampal BDNF expression by increasing the NE/5-HT levels of antidepressants. This has led to the hypothesis that increased BDNF mRNA expression associated with exercise may be initiated by monoaminergic activation. Studies indicate that noradrenaline-mediated signaling may be particularly important in the modulation of the BDNF gene expression through exercise. These results confirm that noradrenaline stimulation is an important initial event in cellular mechanisms, leading to improved BDNF transcription following physical exercise. Together with antidepressants, exercise is thought to have a similar effect on the induction of noradrenaline activation and increase in BDNF via β-adrenergic receptors (Figure 2) (62).

Figure 2.

Relationship between BDNF and glutamate receptors.

Evidence from human and animal studies has shown that monoaminergic hypofunction is a curable component of depression (63). Therefore, antidepressant drugs have been developed to increase serotonergic (5-HT) or noradrenergic (NE) neurotransmission to eliminate the effects of depression.

Seven studies (48–54) in this review reported that aerobic exercise in MDD increased BDNF, and two demonstrated that elevated BDNF was accompanied by improved cognitive functions (48, 49). In the literature, the reduced levels of neurotrophic factors and neurogenesis have been suggested to contribute to the neurotrophic hypothesis of depression (64). It is recommended that antidepressants increase BDNF expression, and in turn, BDNF increases the effect of antidepressants using a similar neurochemical pathway (65). Considering that neurotrophic factors, especially BDNF, can contribute to the treatment of depression, exercise can be used as a therapeutic tool.

It is reported that skeletal muscle secretes cytokine in response to exercise and increases interleukin (IL)-6, which then crosses the blood-brain barrier and triggers BDNF secretion from platelets. BDNF expression in the central nervous system has been found to be strongly associated with the IL-6 level and platelet count (66). During acute exercise, the increase in IL-6 produced by the working muscles inhibits tumor necrosis factor α (TNF-α) and IL-1β expression. Therefore, it is possible that the therapeutic effect of exercise on depressive symptoms may prevent proinflammatory etiology through changes in immune functions.

The peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α also appears to play a role in facilitating the effects of exercise on brain health and is part of the mechanism by which exercise induces hippocampal BDNF expression. Exercise first induces the expression of the estrogen-related receptor (ERR) α gene in the brain, then stimulates PGC-1α expression. The increased activity of the ERRα/PGC-1α complex through exercise induces the expression of the BDNF gene (67). One of the reviewed studies, exercise was reported to have a protective effect against depression by altering the metabolism of the kynurenine (68). The activation of PGC-1α increases the skeletal muscle expression of the aminotransferases of kynurenine, protecting the brain from stress-related changes through the conversion of kynurenine to kynurenic acid, a metabolite that cannot cross the blood-brain barrier, and reducing plasma kynurenine. These studies indicate that PGC-1α in the muscle and brain can mediate the effects of exercise on cognitive functions.

However, three of the reviewed studies showed that aerobic exercise did not cause an increase in BDNF in cases with MDD (69–71). Consistent with these results, a meta-analysis in the literature reported that chronic aerobic exercise did not affect the BDNF level in MDD and suggested that the predominance of female patients in the sample included in the study might have led to this finding (72). The authors reported that the cerebral blood flow, blood volume, and other circulating neurotransmitters might be the cause of the exercise-triggered changes in neuronal life, synaptogenesis, and neural circuitry. In another chronic aerobic exercise study conducted with healthy individuals by the same group of researchers, the findings indicated a rapid increase in the BDNF level in men following exercise, but no changes were observed in women (73).

Effects of Exercise in Schizophrenia

BDNF, which increases the expression of dopamine receptors in the brain by mimicking the effect of antipsychotic drugs, is reported to regress manic mood (74, 75). Similarly, schizophrenia studies have shown that exercise improves cognitive abilities and physical health (2, 76) and that low-level BDNF is associated with negative symptoms and may contribute to the psychopathology of the disease (77).

Since BDNF is widely distributed throughout the central nervous system and plays a role in various psychiatric disorders, impairment in BDNF signaling is not specific to schizophrenia. However, considering the effect of BDNF on the plasticity and neuronal viability of dopaminergic, serotonergic, and cholinergic neurons, and the importance of all these pathways in the pathophysiology of schizophrenia, it can be concluded that BDNF can be a useful biological marker for the clinical status and/or prognosis of people with this disease.

In the schizophrenia studies included in this review (46, 47), the increase in the peripheral BDNF level and the improved cognitive performance findings in response to exercise support the idea that exercise can enhance neurotrophic and neuroprotective mechanisms, and thus leading to an improvement in the symptoms of schizophrenia. One of the possible ways in which aerobic exercise improves the symptoms of schizophrenia is that it enhances drug efficacy by affecting the pharmacokinetics of antipsychotics, for example, by changing drug distribution and reducing drug excretion (78).

BDNF is a neurotrophin that is not only related to neuronal protection and development but also effective in synaptic regulation, learning, and memory. Since BDNF plays an important role in regulating synaptic plasticity, schizophrenia deficits can be understood in the context of learning and the molecular and cellular mechanisms of memory.

Concerning the pathogenesis of schizophrenia, particularly neurodevelopmental and neurotoxicity-related factors, neurotrophins, such as BDNF can provide an explanatory framework at molecular and cellular levels. The synaptic changes that occur due to problems in BDNF expression can alter neurotransmitter pathways that are classically involved in the pathophysiology of schizophrenia; e.g., dopaminergic and gamma-aminobutyric acid (GABA) systems (79, 80). Abnormal BDNF and TrkB mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders showed that the main features of hippocampal signal transmission and plasticity can be affected in these major mental disorders (81).

In patients with schizophrenia, a deficiency in BDNF signaling mediated by receptor TrkB can result in decreased GABA synthesis in the dorsolateral prefrontal cortex. This may lead to a change in the perisomatic inhibition of pyramidal neurons by decreasing the gamma neuron activity at synchronized frequencies required for working memory. Consistent with the literature, Nuechterlain et al. (47) showed that aerobic exercise increased the peripheral BDNF level in patients with schizophrenia and improved working memory findings.

Figure 3.

Reciprocal relationship of BDNF, 5-HT, NE

In negative symptoms of schizophrenia, the mechanism of glutamate dysfunction was implicated, and increased glutamate function was shown to have the potential to reduce such symptoms (82). BDNF can directly alter glutamate signaling by altering the expression of glutamate receptor subunits and Ca²⁺ regulatory proteins. It can also have an impact on glutamate signaling by inducing antioxidant enzyme production, energy regulating proteins, and the members of the antiapoptotic Bcl2 family. Glutamate stimulates BDNF production, which, in turn, affects neuronal glutamate sensitivity, Ca²⁺ homeostasis, and plasticity (83). In the early studies examining the relationship between glutamatergic system and BDNF, mature BDNF was reported to induce the rapid effects of glutamate secretion and the short- and long-term effects of post-synaptic responses to neurotransmitters. A study focusing on the acute effect of BDNF on the hippocampus neurons of rats found that glutamatergic synaptic transmission was increased in 30% of the cells, but this increase was not seen when receptor TrkB was inhibited (84). This data suggests that presynaptic modification is effective in increasing glutamatergic synaptic transmission, and BDNF is involved in this modulation. Although the studies included in this review did not examine the state of negative symptoms in schizophrenia, the improvement in cognitive functions was accompanied by elevated BDNF. This improved clinical state can be explained by aerobic exercise increasing the use of glutamate by the brain.

A decreased serum BDNF level has been shown to correlate with processing speed, attention, executive functions, and poor performance in working memory, and the relationship between serum BDNF and cognitive test performance has been emphasized. In the schizophrenia studies included in this review, the increase in the BDNF level through exercise accompanied by improvement in cognitive functions seems to be consistent with the literature (85, 86). Exercise may be involved in this process through exercise-induced neuronal activity, and it can change cognitive performance findings. Similarly, considering that physical health deterioration associated with the lack of physical activity in schizophrenia reduces the average life expectancy by 10 to 15 years due to suicide, it is possible to comment that exercise also has an effect on life expectancy (87).

Reviewing the Findings on MDD and Schizophrenia Together

Exercise appears to be involved in the development of synaptic plasticity in the adult hippocampus through a BDNF-mediated mechanism. The major area of BDNF expression in the brain is the hippocampus. The findings of the MDD and schizophrenia studies included in this review being more significant for memory performance (47–49, 69) can be interpreted in this context, and the relatively less effect of BDNF on the other cognitive tasks can also be attributed to this. On the other hand, it is known that the BDNF level increases with antidepressant treatment. In one of the studies included in this review that detected an increase in BDNF (52), 80% of the participants used one or more antidepressants. However, in another study in which the participants used antidepressants (71) no increase was detected in BDNF. Therefore, in similar studies, the effect of drug interaction should also be taken into consideration. The contradictory results in the literature may be due to the effect of gender on BDNF responses. It has been reported that gender has an effect on the relationship between the BDNF level and general cognitive functions in schizophrenia, and this relationship is only observed in women (88). In this review, homogeneous groups were not included in the studies examined, and the effect of BDNF and cognitive functions were observed in mixed groups. In aerobic exercise studies, the duration and intensity of exercise can also have an impact on the results. In one study that did not report an increase in BDNF, exercise duration was limited to three weeks, and no data was provided on exercise intensity. Among the chronic aerobic exercise studies included in this review, the longest exercise intervention lasted 12 weeks. Longer regular exercise programs can produce different findings. It should also be kept in mind that increased BDNF responses after exercise may be related to the basal BDNF level of the individual. In future studies, considering the number and function of platelets known to store BDNF can offer new insights. It has been reported that the responses of BDNF to exercise in healthy individuals are affected by a number of different variables, such as age, gender, exercise type, exercise duration, and body mass index (89, 90). Therefore, examining the effect of exercise in psychiatric disorders indicates the need for more homogeneous study groups. In brief, the psychological effect of exercise on cognition is associated with increased autonomic response, physical well-being, and increased quality of life, whereas the mechanism of action of BDNF in this review is evaluated under the framework of a biological basis.

The proposition that BDNF may facilitate improvement in cognitive functions in disorders that involve structural changes to the brain requires further investigation. The limited number of studies we reviewed and the absence of a significant change in the BDNF level in three of the studies (69–71) make it difficult to make a comprehensive generalization on the subject.

CONCLUSION

Although there are studies showing that exercise is protective for brain health, affects cognition and mood, and regresses symptoms in psychiatric disorders, the number of studies discussing cognitive performance and BDNF responses in depression and schizophrenia is limited. Despite all these limitations and contradictory results, there are more studies showing that exercise provides an increase in the BDNF level. Studies examining the cognitive performance findings have obtained data revealing the enhancing effect of exercise, especially on memory responses. Although it does not diminish the importance of traditional therapies, exercise can be considered as a low-cost supportive treatment for MDD and schizophrenia. The dynamic nature of the brain can allow for a positive effect of exercise as an external factor on these disease processes, and support individuals’ functionality in everyday life by increasing their ability to adapt. The promotion of behavioral approaches, such as exercise can contribute to the improvement of the general health state by increasing the general well-being of the person, as well as regressing chronic and treatment-resistant psychiatric disorders. By learning more at the molecular level about the pathways underlying synaptic plasticity, we can go one step further in finding protective and curative ways to ensure brain health, which may also include increasing BDNF. Further studies planned with larger and homogeneous participant groups and different intensity and intensity of exercise will lead the way to providing an understanding of the effect of exercise on the prevention and treatment of psychiatric disorders.