Ketogenic diet as a metabolic therapy for mood disorders: Evidence and developments
Introduction
Mood disorders are a common and prevalent group of chronic mental illnesses. In spite of significant progress in the field of biological psychiatry, mood disorders persist as a major collective challenge, with a substantial negative impact on mental capital (Kessler and Bromet, 2013). Major depressive disorder (MDD) affects 3–17% of all adults at some point in their lifetime, and bipolar disorder (BD) affects between 1 and 3% of general population (Merikangas et al., 2012; Moreira et al., 2017). Mood disorders are heterogeneous both in clinical presentation and in underpinning pathophysiology., which may account at least in part for the substantial inter-individual differences in treatment responses. Approximately one third of patients with MDD will develop clinical presentations characterized by treatment resistant depression (TRD), where patients experience a severe and more progressive clinical course, along with deleterious neurobiological changes. Although there is no consensual definition of TRD, most studies define it as insufficient symptomatic and functional improvement after two successive courses of treatment with at least two different classes of antidepressants at appropriate doses and duration (Fava, 2003). In the same way, it is estimated that about a half of individuals with BD will not be able to achieve symptomatic remission with guideline-guided treatments (Judd et al., 2003).
Recently, two major theoretical advances in the understanding of pathophysiology and clinical presentation of mood disorders had a decisive impact in the field, with promise for advancing our understanding of reasons for treatment resistance. First, the dimensional approach proposed by the Research Domain Criteria (RDoC) project, elaborated and developed by the National Institutes of Mental Health (NIMH), provided a framework for improved understanding of brain function (Insel et al., 2010). In its current form, the RDoC framework proposes five domains of psychopathology, which are defined using the contemporary knowledge about major brain-behavior units of expression of psychopathology. With the RDoC approach, studying the neurobiology of specific domains of depressive symptomatology such as anhedonia, rumination, suicidality, sleep disruption, appetite, among others, has become more acceptable and prioritized over conventional research methods (Heshmati and Russo, 2015; Mandell et al., 2014; Woody and Gibb, 2015)
The second advance in mood disorders was the discovery that classical presentations of recurrent MDD and BD are not only emotional and behavioral but also systemic. Obesity and metabolic syndrome are significant contributors of morbidity and mortality among patients with MDD (Woo et al., 2016; McIntyre et al., 2007). Obesity is one of the principle risk factors for cardiovascular disease and, along with dyslipidemia, hypertension and diabetes, contributes to the metabolic syndrome, which disproportionately affects more than one third of the individuals with MDD (Subramaniapillai and McIntyre, 2017). The high prevalence of metabolic abnormalities in mood disorders as well their role in pathophysiology of the disease have led to proposals that mood manifestations could be understood as an intrinsic expression of a multi-systemic syndrome, affecting the nervous, endocrine and immune systems (Mansur et al., 2015; McIntyre et al., 2007). High body weight, insulin and glucose dysregulation and inflammatory activation in this context could be proxy phenomena of cardiovascular morbidity and mortality (Czepielewski et al., 2013; McIntyre et al., 2009). Nevertheless, few studies have translated these findings in very novel metabolic therapeutic approaches to prevent or treat both psychiatric and systemic manifestations of mood disorders (Cha et al., 2017; Mansur et al., 2017).
Diet interventions present a unique and potentially useful treatment avenue for mood disorders (Wolniczak et al., 2017; Bauer et al., 2016; Sarris et al., 2015). Specifically, diets aiming at weight loss have received growing attention, including intermittent fasting (Kessler et al., 2018), Mediterranean diet (Sanchez-Villegas and Martínez-González, 2013) and caloric restriction (Zhang et al., 2015). The ketogenic diet (KD) is a high-fat, adequate-protein, low-carbohydrate diet. This diet forces the body to use fats rather than carbohydrates as the main energetic source. Normally, the carbohydrates contained in food are converted into glucose, which is the main energetic substrate for the brain. However, if there is little carbohydrate in the diet, the liver will convert fat into fatty acids and ketone bodies. The ketone bodies pass into the brain and replace glucose as an energy source. KD has been recognized as an effective therapy for treatment-resistant neuropsychiatric diseases, including epilepsy since the 1920s (Koppel and Swerdlow, 2017; Nei et al., 2014; Lefevre and Aronson, 2000; Peterman, 1924), mitochondriopathies, alternating hemiplegia of childhood (AHC), brain tumors, migraine, and autism spectrum disorder (ASD) (Verrotti et al., 2017). At least for epilepsy, KD also was reported to be associated with procognitive effects, although it is unclear to which factor this should be attributed to (i.e. the reduction of medications, improvement of depressive and anxiety symptoms) or if this is an independent effect of the diet (Garcia-Penas, 2018).
The objective of this review is to comprehensively assess the potential of KD as a novel/ innovative treatment for mood disorders, critically evaluating data from animal and human studies and discussing the potential of this dietetic intervention for research and clinical care.
Section snippets
Brain effects of ketogenic diet
The most robust data on the potential of KD in the treatment of neuropsychiatric illnesses are derived from studies with epilepsy. Case reports on KD as an intervention to control treatment-resistant seizures, especially in children, are found in the literature throughout the past century (Peterman, 1924). Several observational studies and a meta-analysis revealed that almost half of children and young people with epilepsy on this diet saw the number of seizures drop by at least half, and the
Ketogenic diet and the changes in brain energetic matrix
Interestingly, the mechanisms of action of KD seem to go far beyond the regulation of neurotransmitters (Fig. 1). Data from animal studies indicate that KD is associated with vascular brain changes, increasing vascular density at the blood-brain barrier without changes in blood flow. It has been hypothesized that increases in capillary density with increased plasma ketone bodies would increase in 40-fold the flux of ketonic bodies substrates available for brain energy metabolism (Puchowicz et
Ketogenic diet as a potentially useful therapy for treatment-resistant mood disorders
A therapeutic effect of KD on mood disorders has been described in case reports involving individuals with MDD and BD, usually exhibiting characteristics of treatment resistance (Phelps et al., 2013; Bostock et al., 2017). Although currently there is no randomized clinical trial on KD for the treatment of MDD or BD, especially in the cases in which it could be more useful, such as treatment resistant presentations, several outcomes attributed to KD would be potentially beneficial:
- 1
Reduction of
Future perspectives
Ketogenic diet is a safe (Arya et al., 2018; Taylor et al., 2017), relatively affordable, multi-target intervention with well-defined beneficial systemic effects, but also neurotrophic, antioxidant, neuroprotective and anti-inflammatory properties in the CNS. In the territory of drug discovery, interventions with pleiotropic actions and able to act in critical targets for illnesses trajectory are especially valuable. Ketogenic diet opens a new avenue for investigation of diet as a potential
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