Fasting's Impact on Major Depressive Disorder Examined

Major depressive disorder (MDD) is a serious mental illness that, according to the World Health Organization, will be the leading cause of disease burden by 2030 1 . Due to its multifactorial nature and heterogeneous symptomatology, determining the precise etiology of MDD remains challenging.

An initial hypothesis, based on the proposed cause of action of antidepressant drugs, suggested a decrease in monoamines in the central nervous system as the underlying pathological mechanism of MDD 2. However, despite the availability of a variety of different antidepressants Primarily targeting neurotransmission, these treatment options often do not produce adequate results in terms of response and remission.

In fact, up to 50% of all patients diagnosed with MDD have a therapy-resistant form of the disease, indicating that alternative pathogenic mechanisms , which are not the direct target of classical antidepressant treatment, are likely to contribute to the disease. development and progression of MDD, and that alternative treatment options are needed.

Subsequent imaging studies and meta-analyses proposed that changes in neural plasticity would be critically involved in MDD pathology, and reduced levels of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), were previously reported. English).

Importantly, maintaining neuroplasticity requires adequate energy supply and multiple studies have indicated that caloric restriction increases function and structure in the hippocampal region, while high calorie intake appears to be detrimental and consequently , imaging studies found alterations in brain energy metabolism in the context of MDD.

In this sense, fasting is associated with a strong increase in ketone bodies in the blood, produced and secreted by hepatocytes during gluconeogenesis, which increase in the circulation until the third day of fasting and stabilize thereafter. Ketones constitute a alternative brain energy source and, furthermore, appear to affect brain function by inducing BDNF expression.

Although calorie restriction was shown to affect cognitive function in rodent models according to the protocol, if applied in young animals, as indicated by increased learning and memory capacity, improved motor coordination and general cognitive performance. Additionally, fasting was found to be associated with mood disturbances, including worsening mood, increased irritability, difficulty concentrating, and increased fatigue, as well as an increase in blood pressure scores. depression in mentally healthy humans.

Given the interrelationship of neuronal plasticity and central and peripheral energy metabolism, one could speculate that antidepressant efficacy could be hampered by an adverse central energy situation and that, in turn, a correction of the peripheral and subsequently cerebral energy state, could be a prerequisite to allow maximum effectiveness of antidepressant therapies.

Summary

Major depressive disorder (MDD) is frequently associated with a poor response to treatment. Common antidepressants target neurotransmission and neuronal plasticity, which require adequate energy supply.

Since imaging studies indicate alterations in central energy metabolism and caloric restriction improves neuroplasticity and affects mood and cognition, correction of energy status could increase the effectiveness of antidepressant treatments and reduce psychopathological symptoms of depression. depression.

Metabolic parameters, stress hormones, and brain-derived neurotrophic factor (BDNF) levels were assessed in serum from depressed hospitalized patients (MDD, N = 21) and healthy volunteers (Ctrl, N = 28) before and after a 72-hour fasting period during which only water was consumed.

Depression severity was assessed using the Beck Depression Inventory (BDI)-2 total score and cognitive-affective and somatic subscores.

Fasting similarly affected metabolic parameters and stress systems in both groups. Fasting elevated BDI-2 sum scores and Ctrl somatic subscores.

In MDD, fasting increased somatic symptoms, but decreased cognitive-affective symptoms. Subgroup analyzes based on the sum of BDI-2 scores before fasting showed that cognitive-affective symptoms decreased in patients with moderate/severe symptoms, but not in those with mild symptoms. This was associated with differential changes in BDNF levels.

In conclusion , fasting improved cognitive-affective subscores in MDD patients with moderate/severe symptoms who had not responded to previous therapy.

Discussion

Our study revealed similar effects of a 72-h fasting intervention on peripheral parameters of metabolism and stress systems. With respect to psychometrics, we found that fasting resulted in elevated somatic symptoms as well as overall BDI-2 scores in the healthy Ctrl group.

In patients with MDD, fasting was associated with a comparable increase in the BDI-2 somatic subscore, while cognitive-affective symptoms decreased, resulting in overall comparable BDI-2 total scores before and after fasting. Interestingly, the beneficial effect of fasting on cognitive-affective symptomatology could be attributed to a subgroup of patients who began the fasting intervention with moderate to severe symptoms (BDI-2 score ≥ 19), which was associated with differential regulation of BDNF. circulating levels in this group.

Despite the significant number of psychopharmacological medications available for the treatment of MDD, appropriate guideline-based therapy often fails to achieve response and remission, indicating underlying pathogenic mechanisms that are not the direct target of antidepressant treatment.

Imaging studies point to alterations in brain energy metabolisms in the context of depression.

Given that neurotransmission, as well as the maintenance of neuroplasticity, the main targets of antidepressant drugs, require an adequate energy supply, it seems reasonable that modulation of peripheral and subsequently brain energy status could increase the therapeutic efficacy of the drugs. routinely used antidepressants.