Ketogenic diet as a metabolic therapy for mood disorders: Evidence and developments

https://doi.org/10.1016/j.neubiorev.2018.07.020Get rights and content

Highlights

  • Mood disorders could have metabolic manifestations as part of the psychiatric syndrome.

  • Diet interventions present a unique and potentially useful treatment avenue for mood disorders.

  • Preliminary data suggest a potential role for ketogenic diet in the treatment of mood disorders.

Abstract

Despite significant advances in pharmacological and non-pharmacological treatments, mood disorders remain a significant source of mental capital loss, with high rates of treatment resistance, requiring a coordinated effort in investigation and development of efficient, tolerable and accessible novel interventions. Ketogenic diet (KD) is a low-carb diet that substantially changes the energetic matrix of the body including the brain. It has been established as an effective anticonvulsant treatment, and more recently, the role of KD for mental disorders has been explored. Ketogenic diet has profound effects in multiple targets implicated in the pathophysiology of mood disorders, including but not limited to, glutamate/GABA transmission, monoamine levels, mitochondrial function and biogenesis, neurotrophism, oxidative stress, insulin dysfunction and inflammation. Preclinical studies, case reports and case series have demonstrated antidepressant and mood stabilizing effects of KD, however, to date, no clinical trials for depression or bipolar disorder have been conducted. Because of its potential pleiotropic benefits, KD should be considered as a promising intervention in research in mood disorder therapeutics, especially in treatment resistant presentations.

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

References (97)

  • Y. Genzer et al.

    Effect of dietary fat and the circadian clock on the expression of brain-derived neurotrophic factor (BDNF)

    Mol. Cell. Endocrinol.

    (2016)
  • A.L. Hartman et al.

    The neuropharmacology of the ketogenic diet

    Pediatr. Neurol.

    (2007)
  • M.V. Ivannikov et al.

    Calcium clearance and its energy requirements in cerebellar neurons

    Cell Calcium

    (2010)
  • N. Juge et al.

    Metabolic control of vesicular glutamate transport and release

    Neuron

    (2010)
  • A. Lutas et al.

    The ketogenic diet: metabolic influences on brain excitability and epilepsy

    Trend Neurosci.

    (2013)
  • M. Maalouf et al.

    The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies

    Brain Res. Rev.

    (2009)
  • K.A. MacCracken et al.

    Development and evaluation of a ketogenic diet program

    J. Am. Diet. Assoc.

    (1999)
  • R.B. Mansur et al.

    Selfish brain and neuroprogression in bipolar disorder

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2013)
  • R.B. Mansur et al.

    Is there a “metabolic-mood syndrome”? A review of the relationship between obesity and mood disorders

    Neurosci. Biobehav. Rev.

    (2015)
  • R.B. Mansur et al.

    Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: a pilot, open-label study

    J. Affect. Disord.

    (2017)
  • R.S. McIntyre et al.

    Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach

    J. Affect. Disord.

    (2014)
  • J.B. Milder et al.

    Acute oxidative and systemic Nrf2 activation by the ketogenic diet

    Neurobiol. Dis.

    (2010)
  • H. Möhler

    The GABA system in anxiety and depression and its therapeutic potential

    Neuropharmacology

    (2012)
  • G. Morris et al.

    A model of the mitochondrial basis of bipolar disorder

    Neurosci. Biobehav. Rev.

    (2017)
  • P. Murphy et al.

    The antidepressant properties of the ketogenic diet

    Biol. Psychiatry

    (2004)
  • M. Nei et al.

    Ketogenic diet in adolescents and adults with epilepsy

    Seizure

    (2014)
  • A. Palomino et al.

    Decreased levels of plasma glutamate in patients with first-episode schizophrenia and bipolar disorder

    Schizophr. Res.

    (2007)
  • A. Peters et al.

    The selfish brain: competition for energy resources

    Neurosci. Biobehav. Rev.

    (2004)
  • A.S. Shariq et al.

    Targeting cytokines in reduction of depressive symptoms: a comprehensive review

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2018)
  • R. Uher et al.

    Body weight as a predictor of antidepressant efficacy in the GENDEP project

    J. Affect. Disord.

    (2009)
  • R.F. Villa et al.

    Mitochondrial energy metabolism of rat hippocampus after treatment with the antidepressants desipramine and fluoxetine

    Neuropharmacology

    (2017)
  • A.F. Vizuete et al.

    Brain changes in BDNF and S100B induced by ketogenic diets in Wistar rats

    Life Sci.

    (2013)
  • M.L. Woody et al.

    Integrating NIMH research domain criteria (RDoC) into depression research

    Curr. Opin. Psychol.

    (2015)
  • L.B. Achanta et al.

    β-Hydroxybutyrate in the brain: one molecule, multiple mechanisms

    Neurochem. Res.

    (2017)
  • D. Attwell et al.

    An energy budget for signaling in the grey matter of the brain

    J. Cereb. Blood Flow Metab.

    (2001)
  • M. Balietti et al.

    Ketogenic diets cause opposing changes in synaptic morphology in CA1 hippocampus and dentate gyrus of late-adult rats

    Rejuvenation Res.

    (2008)
  • Y. Bansal et al.

    Mitochondrial dysfunction in depression

    Curr. Neuropharmacol.

    (2016)
  • E.C. Bostock et al.

    The current status of the ketogenic diet in psychiatry

    Front. Psychiatry

    (2017)
  • K.J. Bough et al.

    Anticonvulsant mechanisms of the ketogenic diet

    Epilepsia

    (2007)
  • K.J. Bough et al.

    Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet

    Ann. Neurol.

    (2006)
  • N.N. Danial et al.

    How does the ketogenic diet work? Four potential mechanisms

    J. Child Neurol.

    (2013)
  • O.M. Dean et al.

    Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression

    Rev. Bras. Psiquiatr.

    (2015)
  • N. Dupuis et al.

    Ketogenic diet exhibits anti-inflammatory properties

    Epilepsia

    (2015)
  • J.J. Garcia-Penas

    Epilepsy, cognition and ketogenic diet

    Rev. Neurol.

    (2018)
  • A. Gjedde et al.

    Oxidative and nonoxidative metabolism of excited neurons and astrocytes

    J. Cereb. Blood Flow Metab.

    (2002)
  • R. Grassi-Oliveira et al.

    Interleukin-6 and verbal memory in recurrent major depressive disorder

    Neuro Endocrinol. Lett.

    (2011)
  • M. Heshmati et al.

    Anhedonia and the brain reward circuitry in depression

    Curr. Behav. Neurosci. Rep.

    (2015)
  • T. Insel et al.

    Research domain criteria (RDoC): toward a new classification framework for research on mental disorders

    Am. J. Psychiatry

    (2010)
  • Cited by (96)

    • Mitochondrial dysfunction: A fatal blow in depression

      2023, Biomedicine and Pharmacotherapy
    View all citing articles on Scopus
    View full text