Register or Submit a manuscript.
Quick Link
OBM Integrative and Complementary Medicine

(ISSN 2573-4393)

OBM Integrative and Complementary Medicine is an international peer-reviewed Open Access journal published quarterly online by LIDSEN Publishing Inc. It covers all evidence-based scientific studies on integrative, alternative and complementary approaches to improving health and wellness.

Topics contain but are not limited to:

  • Acupuncture
  • Acupressure
  • Acupotomy
  • Bioelectromagnetics applications
  • Pharmacological and biological treatments including their efficacy and safety
  • Diet, nutrition and lifestyle changes
  • Herbal medicine
  • Homeopathy
  • Manual healing methods (e.g., massage, physical therapy)
  • Kinesiology
  • Mind/body interventions
  • Preventive medicine
  • Research in integrative medicine
  • Education in integrative medicine
  • Related policies

It publishes a variety of article types: Original Research, Review, Communication, Opinion, Comment, Conference Report, Technical Note, Book Review, etc.

There is no restriction on paper length, provided that the text is concise and comprehensive. Authors should present their results in as much detail as possible, as reviewers are encouraged to emphasize scientific rigor and reproducibility.

Indexing: DOAJ-Directory of Open Access Journals.

Publication Speed (median values for papers published in 2023): Submission to First Decision: 5.9 weeks; Submission to Acceptance: 14.7 weeks; Acceptance to Publication: 8 days (1-2 days of FREE language polishing included)

Current Issue: 2024  Archive: 2023 2022 2021 2020 2019 2018 2017 2016
Open Access Review

Exploring the Rationale for the Use of the Ketogenic Diet in the Treatment of Mental Health Disorders

Joseph V. Pergolizzi 1, †, Aaron Tabor 2, †, Jo Ann LeQuang 1, †, Michael Annabi 1, †, Hani Annabi 3, †

1. NEMA Research, Inc., Naples, Florida, USA

2. Best Medicine, LLC, Winston-Salem, North Carolina, USA

3. Texas Tech University Health ScienceCenter, El Paso, Texas, USA

† These authors contributed equally to this work.

* Correspondence: Jo Ann LeQuang

Academic Editor: Gerhard Litscher

Received: June 05, 2019 | Accepted: October 28, 2019 | Published: November 05, 2019

OBM Integrative and Complementary Medicine 2019, Volume 4, Issue 4, doi:10.21926/obm.icm.1904062

Recommended citation: Pergolizzi JV, Tabor A, LeQuang JA, Annabi M, Annabi H. Exploring the Rationale for the Use of the Ketogenic Diet in the Treatment of Mental Health Disorders. OBM Integrative and Complementary Medicine 2019; 4(4): 062; doi:10.21926/obm.icm.1904062.

© 2019 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Background: The ketogenic diet (KD) was developed in the 1920s as a treatment for pediatric epilepsy and is emerging as a possible treatment option for certain mental health disorders. There is a link between certain mental health disorders and epilepsy, suggesting some commonality among underlying mechanisms.

Methods: The literature relating to mental disorders and the KD is sparse. The authors attempt to a narrative review of the existing literature to show that there may be validity to studying the KD as a treatment for certain mental health disorders.

Results: Various types of mitochondrial dysfunction and impaired oxidative metabolism have been identified in many mental health disorders (bipolar disorder, major depressive disorder, autism, schizophrenia, and others). Mitochondrial deficits may affect neuroplasticity and cause synaptic dysfunction, which could change brain structure and function in a way that might affect behavior. The KD has been associated with epigenetic changes in the genes associated with mitochondrial function. Chronic oxidative stress and inflammation have also been implicated in mental health disorders and may be reduced by the KD. The KD regulates glutamatergic transmission and may initiate extracellular changes as well, in a manner similar to pharmacological agents used to stabilize moods. The KD may be difficult for patient adherence and has been associated with many and potentially severe adverse effects. The role of the KD in addressing treatment-resistant pediatric epilepsy is established and epilepsy is comorbid with a number of mental health conditions.

Conclusions: There is a paucity of literature on this subject and there is no robust clinical evidence in support of the use of the KD for treating mental disorders but there are indications that the KD can reduce systemic inflammation, improve cerebral mitochondrial metabolism, and enhance endogenous antioxidation, all of which may be helpful in treating certain mental health conditions. The KD is also associated with serious health risks and clinicians must weigh risks versus benefits.

Keywords

Diet; ketogenic diet; ketosis; mental health disorder; mitochrodrial dysfunction

1. Introduction

Developed in the 1920s as a treatment for pediatric epilepsy, the ketogenic diet (KD) is a high-fat, low-protein/low-carbohydrate diet, often described in terms of the ratio of lipids to non-lipids, ranging from 2:1 to 6:1. [1] The 4:1 KD showed more antiepileptic benefit in a study of 76 patients with refractory childhood epilepsy compared to the 3:1 KD diet, although patients with fewer gastrointestinal (GI) symptoms better tolerated the latter. [1] A Cochrane review of randomized clinical trials showed that the KD showed promising results for treating pediatric epilepsy, albeit with certain GI side effects. [2] With the advent of anticonvulsant therapy in the late 1930s, the KD fell out of favor until it regained recognition in the 1990s as a potential treatment option for drug-refractory epilepsy. [3] Less rigorous variations on the KD are popular among consumers for weight loss.

In addition to its role in the treatment of pediatric epilepsy, the KD is emerging as a possible treatment option for certain mental health conditions. There is a well-established link between certain mental health disorders and epilepsy, [4] which suggests that there may be some commonality in terms of underlying mechanisms. Evidence suggesting that certain mental health disorders may have an underlying metabolic mechanism suggest the possible role of diet-based therapy. The KD is controversial in that it is associated with potentially severe side effects and the safety of the diet must be considered for each individual patient and balanced against potential benefits. From a scientific point of view, it is important to better understand if and how the KD might address symptoms of certain mental health disorders if only to better understand the mechanisms of these disorders.

The objective of this narrative review is to survey the literature for the current status of research on the possible role of the KD in the treatment of certain mental health disorders.

2. Materials and Methods

This is a narrative review exploring the rationale behind the possible use of the KD in the treatment of certain types of mental health disorders. The KD has known risks and safety must be considered before embarking on this diet for mental health or other conditions.

3. Results

3.1 The Brain’s Response to the Ketogenic Diet

The KD causes ketones (acetone, acetoacetate, and beta-hydroxybutyric acid) to increase [5] and glucose to deplete, causing the body to enter ketosis. Restricted intake of carbohydrates promotes fatty acid oxidation and subsequent conversion into ketone bodies, which then acts as the primary energy source in place of glucose. Evidence of ketosis can be obtained by a simple urine test. (Diet-induced ketosis should be distinguished from ketoacidosis caused by starvation, alcohol toxicity, diabetes, and other conditions; the latter is a potentially life-threatening condition. [6]) Ketone bodies are efficient energy producers. [7]

The human brain requires large amounts of energy for housekeeping functions, maintaining resting and action potentials, and for synaptic transmissions. [8] As much as half of all energy in the brain is dedicated to housekeeping tasks. [9] The brain’s constant or cyclical release of neurotransmitters and neuropeptides consumes energy as well. [9] Despite these high demands, the brain stores comparatively low reserves of glucose and lipids in comparison to other tissues composed of myocytes and adipocytes, respectively. With a typical Western diet, the brain depends almost exclusively on glucose for its energy while the body’s periphery may use fats as well as glucose for fuel. The “selfish brain theory” posits that when glucose supplies are low, the brain prioritizes its need for glucose above all other areas of the body. [10] Eating in accordance with the KD forces the brain to use ketone bodies as its main source of energy, diverting it away from glucose and launching various enzymatic cascades that fundamentally change how the brain metabolizes fuel. It has been proposed that an increase in acetone levels in the brain might reduce seizures due to the anticonvulsant effects of acetone. [11]

3.2 The Brain, the Ketogenic Diet, and Mental Disorders

To meet its consistent high demand for energy, the healthy brain relies on glucose as its primary source of fuel, using mitochondrial functions to convert glucose into the usable energy form of adenosine triphosphate (ATP). Various degrees of mitochondrial dysfunction and impaired oxidative metabolism have been identified in certain mental health disorders including bipolar disorder, depression, autism, schizophrenia, and others. [12] Oxidative stress appears to be one of the primary contributors and possible cause of mitochondrial dysfunction. More specifically, the lack of oxidizing agents lowers the availability of electronic acceptors during oxidative phosphorylation, thereby diminishing the electrochemical gradient needed to drive ATP production in the mitochondria. Mitochondrial deficits may play a role in neuroplastic and synaptic dysfunction, may change brain structure and function, and, in that way, could affect behavior. [13] Chronic oxidative stress is present in certain mental disorders, which are likewise associated with both chronic inflammation and a high level of circulating proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). [12]

Mitochondrial dysfunction, generally classified as either a cytopathy or an encephalomyopathy, arises due to mutations in the mitochondrial DNA or nuclear DNA, the pathways of which are currently being elucidated. [12,14] In a healthy state, the antioxidative efforts of glutathione (GSH) and thioredoxin help clear out reactive oxygen species (ROS) and reactive nitrogen species (RNS), both of which result naturally from the body’s oxidative phosphorylation process. [15] When GSH and thioredoxin are unable to clear ROS and RNS, chronic oxidative stress develops. This may be exacerbated by the activation of certain inflammatory cells, such as microglia, which may stimulate the further production of ROS and RNS. [16] In turn, oxidative stress launches transcription factors, such as NF-Κβ and activated Protein 1, which produce proinflammatory cytokines and other species, which then activate other cells to produce more ROS and RNS in the form of superoxide, nitric oxide (NO), and peroxynitrite. [17,18] This forms the “autotoxic loop” [18] in which chronic inflammation is maintained as a result of proinflammatory cytokines. [19] See Figure 1. In this way, chronic oxidative stress is linked with chronic systemic inflammation. [18] Once chronic inflammation is well established in the periphery, it is hypothesized that inflammatory signals to the brain are transmitted based on the observation that systemic inflammation can lead to chronic neuroinflammation. [20,21] Proinflammatory cytokines may use any of several pathways to the brain, including the vagus nerve, endothelial cells of the blood-brain-barrier, or possible transport by way of circumventricular organs, such as portions of the pituitary gland for example, which lack a barrier to the brain. [22,23]

Figure 1 The autotoxic loop demonstrates the link between oxidative stress and chronic inflammation (Art courtesy of Todd Cooper).

The KD has been or is being explored for a potential role in the treatment of many conditions, including amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and others. [5] The KD has been proposed for autosomal dominant polycystic kidney disease. [24] The underlying assumption is that cellular energy status is involved in many disorders and aberrant energy production has been associated with heart disease, [25] aging, [26] epilepsy, [27] Alzheimer’s disease, [28] and cancer. [29] Energy production and metabolic pathways may likewise be involved in mental health disorders, such as bipolar disorder, depression, schizophrenia, [30] autism spectrum disorder, [31] and attention deficit hyperactivity disorder. [32] Circulating ghrelin is available as acyl ghrelin and des-acyl ghrelin which play different roles. In a murine study, des-acyl ghrelin has an anxiogenic effect on non-stressed animals, but under stress, the effect changes to an anxiolytic effect. [33] The KD decreases the levels of plasma of both acyl and des-acyl ghrelin in pediatric patients. [34] The role of ghrelin in psychiatric disorders, in particular anxiety, is being elucidated. [35]

The KD regulates glutamatergic transmission and controls glutamatergic toxicity by inhibiting vesicular glutamate transport vesicles. [36] The KD may also increase gamma-aminobutyric acid (GABA) and GABAergic transmission, which has been associated with anxiolysis. [37] The KD has been associated with epigenetic changes in genes associated with mitochondrial function [38,39,40] but further work is needed to elucidate the effects of the KD on mitochondrial biogenesis. Cerebral hypometabolism is a characteristic of several mental disorders, including depression. [41] Ketosis may also cause certain extracellular changes which would decrease intracellular sodium levels, thereby steadying the resting state of the action potential, which is a property of many mood-stabilizing agents. [41]

3.3 Mental Disorders and Brain Energy Metabolism

Mental disorders in the United States and other countries remain prevalent conditions, a substantial burden on the healthcare system, and a source of personal distress and societal loss. Safe, effective, broadly reliable treatments for these disorders have proven elusive and many such disorders resist treatment. In fact, treatment-resistant depression (TRD) is a well-known condition, which is by definition intractable. Even with diligent efforts and the advantages of modern healthcare, many patients with mental health disorders never achieve symptomatic remission. [42] While the KD has been suggested for its role in treating mental health disorders, there are comparatively few studies, no large controlled trials, and relatively little scientific attention. [5]

The Research Domain Criteria (RDoC) by the National Institutes of Mental Health (NIMH) offers a new framework for the study of mental health conditions by defining specific cognitive and motivational domains of brain function that allow mental health conditions to be more systematically evaluated. [43] RDoC attempt to blend neurobiological with psychological factors, [44] and have been challenged for their “biological fundamentalism.” However, the RDoC have led to a neurobiological exploration of anhedonia, appetite depression, sleep disorders, and suicidal ideation. For example, recent work by Hesmati and Russo suggest that anhedonia, a core symptom of major depressive disorder (MDD), may be associated with dysregulation of the mesolimbic dopamine (reward) circuit. [45] This theory has recently been extended to anhedonia in schizophrenia, although the latter’s mesolimbic dopamine dysfunction is characterized more by disorganization rather than the deficiency typical in MDD. [46,47] This has led to the recognition that many mood disorders have a systemic component or even a systemic foundation. A few associations have been unexpected, such as obesity and MDD (metabolic syndrome affects both populations at disproportionately high rates). [48] Thus, the symptoms of MDD may be explicable and controllable when approached systemically, which opens the door to potential dietary interventions.

There is a paucity of literature relating to human studies of the KD and various mood disorders and even preclinical research is limited. [5] Yet there are reasons to think the KD may have some promise in the treatment of some of these disorders, for example treating anxiety, depression, bipolar disorder, autism spectrum, attention deficit disorder, and schizophrenia spectrum disorders. Mental health disorders and epilepsy are often comorbid and appear to share some of the same underlying mechanisms. Anecdotal evidence and clinical observation have reported that when the KD is used for control of epilepsy in a patient with mood disorders, the mental health improves as well. Some of these d disorders will be discussed briefly below. Medication therapy is available for many of these disorders with varying degrees of safety and effectiveness. See Tables 1, 2, and 3.

3.3.1 Anxiety Disorders

Various anxiety disorders are identified in the literature: generalized anxiety disorder, social anxiety disorder, and panic disorder. People with generalized anxiety disorder are excessively anxious about daily events in multiple domains of life (home, work, finance, social), typically manifesting in physical symptoms (stomach pain, restlessness, headaches, and so on). [49] On the other hand, panic disorder is episodic and may occur with or without a distinct trigger. Panic attacks are characterized by a trigger and the rapid onset of intense fear, typically lasting about ten minutes. Physical symptoms (trembling, dyspnea, tachycardia, dizziness, nausea, and others) may accompany the episode. People with panic disorder may become overly preoccupied with their condition and live in such fear of another episode that they modify their behavior and limit their social interactions to avoid putting themselves at risk of a new episode. [49] There is considerable overlap in the incidences of various anxiety disorders and epilepsy, in that the lifetime incidence of anxiety is 11.2% in people without epilepsy and 22.8% in people with epilepsy. [50] The 12-month prevalence of generalized anxiety disorder among U.S. adults (age range 18 to 64 years) is 2.9% with a lifetime prevalence of 7.7% for women and 4.6% for men. In contrast, the 12-month prevalence for panic disorder among U.S. adults is 3.1% and lifetime prevalence is 7.0% for women and 3.3% for men. [51]

Cognitive behavioral therapy is the first line of treatment for anxiety disorders, which may be supplemented by pharmacological therapy, such as with benzodiazepines. [49] While the etiology of anxiety disorders remains to be elucidated, evidence suggests anxiety can be associated with unusual brain activitiy, variations in brain structure, altered neuronal processes, and genetic factors. [52] Functional magnetic resonance imaging (fMRI) studies show that anxiety directs blood flow toward the ventromedial prefrontal cortex and hippocampus. [53]

Table 1 Short overview of mental disorders and their most commonly prescribed pharmacological treatments. Note that off-label prescribing is not unusual in the pharmacological treatment of mood disorders. [41,50,54,55,56,57,58,59,60,61,62,63,64,65]

Table 2 Commonly prescribed pharmacological therapies and current indications. Note that there is frequent off-label prescribing of drugs for mental health disorders. [66,67,68] The list is alphabetized by drug name. Brand names are those used in the U.S.; these drugs may be marketed under other brand names in other markets.

Table 3 Frequently prescribed pharmacological treatments for various mood disorders and safety considerations. Most of these drugs carry at least one black-box warning.

 

It is thought that anxiety involves dysfunctional neurotransmission, in that the nervous system’s healthy balance of GABA to glutamate is disrupted; glutamate causes neuronal hyperexcitability which may manifest into symptoms of anxiety and GABA acts to counterbalance these excitatory effects. [69] GABA is the body’s primary inhibitory neurotransmitter and, as such, is present in high concentrations in all regions of the brain and spinal cord (about a third of all CNS neurons are GABAergic) but is not present outside of the central nervous system (CNS). GABA acts on three types of receptors: GABAA, GABAB and GABAC, of which GABAA is known to play a role in anxiety, epilepsy, alcoholism, and other psychiatric disorders. [70] The GABAA receptor may be modulated by the effects of endogenous neurosteroids as well as endogenous or exogenous benzodiazepines. [71]

3.3.2 Depressive Disorders

According to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) types of depressive disorder include disruptive mood dysregulation disorder, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance-induced depression, and major depressive disorder (MDD). MDD is prevalent, one of the most severe forms of depression, and may potentially be treated with the KD. Symptoms of MDD include diminished interest in life, decreased pleasure, weight changes, insomnia or hypersomnia, fatigue, feelings of worthlessness or guilt, difficult concentrating, and suicidal ideation. The 12-month and lifetime prevalence of MDD from the DSM-5 is 5.28% and 13.23%, respectively (95% confidence interval [CI], 12.64-13.81). MDD has significant comorbid associations including substance use disorder, panic disorder, generalized anxiety disorder, and other personality disorders. [61] Depressive disorders occur frequently in people with epilepsy, with a reported prevalence of 11% to 62%. [72,73]MDD may deteriorate into treatment-resistant depression with associated profound and clinically severe changes in neurological function as well as related dysfunction. Treatment-resistant depression lacks a consensus definition but is a recognized clinical entity. [74]

It has been observed that MDD patients have elevated levels of interleukin-1β (IL-1β), TNFα, and IL-6 which suggest both inflammation and increased macrophage activity. [75,76,77] There may be specific groups of MDD patients in which other types of cytokines are more dominant. [78] Oxidative stress is considered a major contributor to MDD, which leads to elevated production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) which, in turn, compromise the body’s antioxidative defenses. [79] MDD patients are observed to have deficient stores of vitamin E, [80] higher lipid peroxidation in the brain, [81,82] and oxidative damage to peripherally circulating lipids. [65,66,67,68,69,70] In patients with MDD, the oxidative stress markers in the periphery have been observed to correlate to the duration and severity of the depressive disorder. [82,84,85] Chronic inflammation has been associated with MDD and remission of depression is characterized by a return to more normal inflammatory markers, such as cytokine levels. [86] Many diseases with an inflammatory component (such as cardiovascular disease, autoimmune disorders) or inflammatory conditions (postpartum period) have been associated with clinical depression. [87]

The KD’s effect on systemic inflammation might be a partial explanation for current interest in its use in the treatment of people with MDD. A preclinical study found that rats on the KD exhibited fewer signs of depressive behavior. [88]

3.3.3 Bipolar Disorder

Bipolar disorder is a biphasic disorder in which symptoms wax and wane with alternating energy levels, which may offer the clearest observable correlation with mitochondrial energy fluctuations. For example, the manic phase of bipolar disorder is characterized by increased brain energy while the depressed phase corresponds to decreased brain energy. [89] Mitochondrial dysfunction underlies a variety of mental health conditions (autism, anxiety disorder, dementia, Down syndrome, depression, and others) and many such conditions are comorbid with each other (for example, depression and dementia). [90] Mitochondria produce the energy necessary for brain function, allow synaptic plasticity, produce important molecules (such as hormones), and oversee the housekeeping of neurotransmissions. When mitochondria malfunction, individuals may exhibit cognitive deficits, intellectual disability, mental health disorders, and/or neurodegenerative disease. [90] Bipolar patients have been observed to have a higher prevalence of mitochondrial disorders than the general population [91], abnormalities in brain and lymphocyte distribution of mitochondria as well as aberrant mitochondrial morphology. [92] In fact, mitochondrial dysfunction is emerging as a new target for drug development in the treatment of bipolar disorder. [38]

Elevated levels of C-reactive proteins have been observed in acute mania and remission phases of bipolar disorder. [93] A meta-analysis found bipolar patients had higher concentrations of tumor necrosis factor-alpha (TNFα) but not higher levels of other cytokines, such as various interleukins, transforming growth factor-beta 1 (TGF-β1) and TNF2. [94] There may be a role for anti-inflammatory agents in the treatment of bipolar disorder and certain omega-3 fatty acids, curcumin, and other substances are being investigated. [95] People with bipolar disorder have been observed to have altered levels of catalase (CAT), superoxide dismutase (SOD), and glutathione. [96] Compared to controls, people with bipolar disorder have greater lipid peroxidation, more damage to the DNA and RNA, and elevated nitric oxide (NO) levels. [97] Furthermore, evidence suggests that the severity of the disorder is correlated to the severity of oxidative stress. [98,99] Improved oxidative defenses and reduction in oxidative stress have been linked with remission in bipolar disorder. [100]

Bipolar disorder is often treated with certain medications aimed at reducing convulsions, such as carbamazepine, valproate, and lithium. However, the anticonvulsants gabapentin and pregabalin do not appear to be effective in treating bipolar disorder. [41] Two case studies in the literature describe patients diagnosed with bipolar disorder who went on the KD and maintained ketosis for a minimum of two years, over which time their bipolar symptoms improved to the extent that they could discontinue their mood-stabilizing drug regimen. [101]

3.3.4 Autism Spectrum Disorder

The DSM-5 describes autism spectrum isorder as a neurodevelopmental disorder characterized by persistent deficits in social (verbal and nonverbal) communication and social interaction and narrowly restricted, repetitive patterns of behaviour, interests, and activities. It is diagnosed four times more often in males than females. In searching for a better understanding of the physiology associated with autistic behaviors, the bidirectional microbiota gut-brain axis has emerged as an intriguing area for research. GI symptoms and alterations in the gut microbiota frequently parallel cerebral disorders. [102] The gut microbiome may be involved in the pathogenesis of autism spectrum disorder and is considered an important new therapeutic target. [103] In fact, the gut microbiome could play a role in the production, expression, and turnover of neurotransmitters, such as GABA, serotonin, and others. [103]

Abnormal expression of pro- and anti-inflammatory cytokines have been observed in the brain, gut, and peripheral blood of children with autism. [104,105,106,107,108,109,110] Likewise, disorders of the immune system have been observed in children with autism, [110,111] along with chronic oxidative stress. [112,113,114] In about 30% to 50% of children with autism, particularly those with more severe forms, there is evidence of mitochondrial dysfunction. [114,115,116,117] Both metabolic and mitochondrial dysfunction underlie autism and epilepsy, although the exact relationship between autism and epilepsy remains to be elucidated. [118,119] About 30% of children with autism have epilepsy; conversely, about 15% to 30% of children with epilepsy have autism. [120,121] While epilepsy is not a causative factor for autism, epilepsy and autism share certain neuronal networks. [118] Genetic mutations in the GABAA receptor subunit have been identified in children with epilepsy and autism, leading to the hypothesis that dysfunctions in GABAergic signaling are a common molecular mechanism in both epilepsy and autism. [122] It has been hypothesized that the KD would provide certain neuroprotective benefits for people with autism although to date no large-scale randomized studies have been conducted. [123]

3.3.5 Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder, involving neuropsychological deficits (including working memory, self-regulation of affect, internalization of speech, and behavioral analysis) combined with a lack of behavioral inhibitions. [124] It occurs in about 29% of pediatric epileptic patients, making it the most frequently reported mental health condition among children with epilepsy. [125] There is an approximately equal sex distribution of ADHD in patients with epilepsy, but ADHD is three or more times more common for males in the general population. [126] It has been observed that when children with epilepsy went on the KD to improve their seizure symptoms, there was a marked improvement in their ADHD symptoms as well. [127] To date, most studies on the relationship of the KD and ADHD have been carried out in animals. [32,128,129]

3.3.6 Schizophrenia Spectrum

The DSM-5 defines schizophrenia spectrum, along with other psychotic disorders, by abnormalities in one of more of the following five domains: delusions, hallucinations, disorganized thinking (speech), grossly disorganized or abnormal motor behavior, i.e., catatonia, and negative symptoms such as anhedonia, lack of emotional affect, and severely curtailed speech and movement. The relationship between schizophrenia and epilepsy remains to be elucidated. Neuroinflammation has been implicated in the etiology of schizophrenia [130,131] and immunological defects have been observed in these patients. [132] The role of Th-17 cells in schizophrenia is being elucidated. [131] Chronic systemic inflammation occurs in schizophrenia and it is thought that the greater degree of inflammation and oxidative stress, the greater the degree of cognitive impairment in the first schizophrenic episode. [133] Patients with schizophrenia have oxidative damage to their DNA, [134,135] overproduction of ROS and RNS, decreased antioxidative defenses, [136] and oxidative stress in the brain and cerebrospinal fluid[137] as well as in the plasma and the periphery. [138,139,140] See Figure 1.

Mitochondrial dysfunction and energy dysregulation may play a role in the etiology of schizophrenia and schizoaffective disorder. [141] Ultrastructural abnormalities in the mitochondria have been observed in schizophrenic patients, [142] with enlarged mitochondria and morphological changes in the organelles of brain and peripheral blood cells. [143,144] Brain energy levels can be affected in people with schizophrenia by NO’s effect on mitochondrial activity, ATP production, [145] and the formation of peroxynitrite, which causes oxidative damage to mitochondrial structural proteins and enzymes as well as damage to membrane lipids. [14,146,147] Most pharmacological treatments for schizophrenia treatment suppress dopamine, but medications are not effective for all patients and are associated with side effects, which may be severe. [148] The majority of patients with schizophrenia are obese, [149] although the possible association of schizophrenia and obesity remains to be elucidated.

The literature reports case studies on two patients with schizoaffective disorder found symptoms decreased when the patients went on the KD, returned when they went off the diet, and decreased again with resumption of the KD. [150] One of these patients was a 33-year-old man who reported a dramatic decrease in auditory hallucinations and delusions, and an improved mood and higher energy level after three weeks on the KD. Maintaining the diet (with a few breaks when symptoms returned) allowed him to make other positive changes in his life as well, in that he was able to complete some online studies, move into his own apartment, and start dating. [150] In another case report, a 70-year-old woman experienced resolution of long-standing symptoms of schizophrenia with the use of the KD. [151] Large-scale randomized clinical trials have not been conducted for more authoritative levels of evidence. It has been proposed that the KD shifts the brain’s ratio of GABA to glutamate in favor of GABA; GABA production in the brain is disrupted in schizophrenics. The shift occurs by suppressing catabolic reactions and increasing GABA synthesis. Furthermore, ketosis may activate brain astrocyte metabolism, subsequently promoting glutamate breakdown/removal while enhancing the conversion of glutamine to GABA. Thus, the KD may help increase cerebral GABA levels and, in that way, reduce schizophrenic symptoms. [152]

3.4 Safety of the Ketogenic Diet

Some may associate ketosis—the assumed and expected result of following the KD—with hyperketonemia, which can be lethal in in extreme circumstances. Pathological ketoacidosis typically occurs in patients with Type I diabetes and differs from what might be called the “physiological ketosis” induced by dietary changes like the KD. Ketogenic changes in human metabolism are unique to our species and likely exist to help humans cope with famine by decreasing glucose demand and insulin levels during periods of deprivation. The KD artificially creates such “famine” conditions while still allowing reasonable caloric intake; similar changes can be brought about by fasting for several days or stark caloric restriction. [153]

Although lifestyle changes such as major dietary modifications are thought to be relatively benign interventions, safety must still be considered. This is particularly important with the KD. Diets that restrict carbohydrates may be problematic in that they typically result in a lower intake of vegetables, grains, and fruits, all of which have recognized nutritional benefits for overall health. [154,155] Adverse effects of the KD include GI problems (which typically are worst in the first weeks of the diet and gradually diminish over time), hyperlipidemia, [156] and renal calculi. [157] Cardiovascular adverse effects are recognized as well, in that QT-interval prolongation on an electrocardiography (ECG) has been reported in up to 15% of pediatric patients on the KD and is potentially arrhythmogenic. [158]

The role of macronutrients in heart health remains controversial. The Prospective Urban Rural Epidemiology (PURE) study was a large epidemiological cohort study of dietary intake of 135,335 individuals in 18 nations with a mean follow-up of 7.4 years. [159] It found higher carbohydrate intake was associated with an increased risk of total mortality but not the risk of cardiovascular morbidity or mortality. A cross-sectional analysis of the PURE study (n=125,287) reported that reducing the intake of saturated fatty acids and replacing them with carbohydrates had an adverse rather than beneficial effect on serum lipid levels. [160] However, a study of 15,428 U.S. adults reported that diets both high and low in carbohydrates were associated with increased mortality and that diets the least risk was associated with diets offering a 50% to 55% total carbohydrate intake. [161] Studies about low-carbohydrate diets in general and the KD in particular are sometimes confounded by the ratio of saturated to unsaturated fat consumption (which is thought to play a potential role in making some diets healthier than others) and the limitation that studies are often short term. A meta-analysis of 40 studies (n=1,141 obese patients) reported that low-carbohydrate diets were effective in causing significant weight and body mass index (BMI) reduction, reduced systolic and diastolic blood pressure, and reduced plasma triglycerides and increased high-density lipoprotein cholesterol; all of which are considered favorable. [162] However, many of these benefits are framed within the context of obese individuals seeking weight loss and its attendant health benefits; it is not clear if these diets would have the same advantageous cardiac benefits in normoweight or underweight individuals.

Adherence to the KD can be challenging, as it demands rigorous attention to food preparation, unusual food combinations and eating patterns, large categories of restricted foods, and a limited ability to dine out. Poor or erratic adherence to the diet may diminish the depth and consistency of ketosis the patient experiences. [163] Testing strips available over the counter may be used for at-home urine tests to confirm ketosis. Overall, for motivated patients (or their caregivers) and under supervision of a physician, the KD may confer benefits on appropriate patients with certain types of mental disorders. [164] Its benefits include its neuroprotective, antioxidant, and anti-inflammatory effects on the central nervous system. [74]

Despite the possibility that the KD may be a nonpharmacological treatment modality or an adjunctive therapy for mental health conditions, studies have been few, small, and typically uncontrolled. Those studies of the KD in the literature rarely report serum ketone levels or ketone levels in urinalysis, making comparisons across studies difficult. Many mental health conditions make dieting difficult in that they are associated with mania, impulsivity, recklessness (meaning patients will likely abandon the diet), or profound apathy, while certain mental conditions may reduce appetite or trigger binge eating. The KD can be extremely demanding for patients, so adherence is likely imperfect. Clinicians must assess relative risk versus benefits for this sort of intervention in an individual patient. Comparative evaluations are challenging in that there is no “standard KD” and metrics for mental health outcomes can vary among studies. See Table 4.

Table 4 A basic overview of the standard ketogenic diet. Note that there are variations of the keto diet such as the “cyclic keto diet” and “targeted keto diet” and others which allow strictly controlled increases in carbohydrates in advance of exertion. To date, there is no universally recognized standard keto diet but the following table describes broad general rules for ketogenic eating. On the standard keto diet, 75% of calories come from fats, 20% from protein, and 5% from carbohydrates. To achieve and maintain ketosis most dieters restrict their total carb intake to 50 g/day. Dieters can also count “net carbs” which are to total carbohydrates minus the fiber; daily intake of net carbs should be 25 g/day.

4. Discussion

The KD has long been recognized as a treatment option for refractory pediatric epilepsy. Its possible role in the treatment of mental disorders may be clinically helpful and suggests that epilepsy and mental health disorders share certain commonalities that may one day help elucidate the pathogenesis of these seemingly diverse and heterogenous conditions. The metabolic dysfunction apparent in both epilepsy and certain mental health disorders is intriguing. Obesity and metabolic syndrome have both been correlated with refractory mental disorders. [165] One suggested explanation for this connection is that a high BMI is associated with increased inflammation which can worsen mental disorders; obesity may also result in disturbed sleep, pharmacokinetic alterations, and reduced bioavailability of prescribed antidepressants. [166] Mitochondrial metabolism increasingly emerges as a factor in both mental disorders and epilepsy. As the KD is further evaluated for its potential benefits in the treatment of mental disorders, a clearer picture may emerge of the pathogenesis of such disorders and their relationship to inflammation, mitochondrial function, and cerebral metabolism.

The KD appears to have the capacity to reduce chronic systemic inflammation and stimulation the endogenous antioxidant defense system. [167] It appears that its anti-inflammatory effect which may be beneficial in the treatment of refractory mental disorders. [168,169] The role of specific anti-inflammatory and proinflammatory cytokines in mood disorders and epilepsy is not yet elucidated. However, the safety of the KD must also be considered in that it is associated with cardiovascular risks, calculi, hyperlipidemia, and GI symptoms. For certain patients with treatment-resistant mental health disorders or those who find the safety and tolerability of available pharmacological therapy unacceptable, the KD may be a consideration. This topic deserves greater scrutiny as it may shed light on functional processes within the brain associated with specific mental disorders.

5. Conclusions

The KD has long been used as adjunctive therapy for treatment-resistant pediatric epilepsy. Epilepsy is comorbid with a number of mental health conditions, including but not limited to MDD, ADHD, autism spectrum disorder, anxiety disorders, and other and it has been anecdotally observed that patients on the KD with a comorbid mental health disorder achieve symptomatic relief of the latter while on the diet. Despite a lack of robust clinical evidence in support of the KD in mental health disorders, there are reasons to consider that a diet that reduces systemic inflammation, improves cerebral mitochondrial metabolism, enhances endogenous antioxidation, and reduces obesity might be helpful for treating certain psychiatric disorders.

Acknowledgments

The authors acknowledge the work of Todd Cooper of Coyote Studios in Green Valley, California for his assistance in creating the art work for the autotoxic loop. The authors wish to thank Dr. Darren Clair for his critical assessment of the manuscript and for his insights into the risks of the ketogenic diet.

Author Contributions

JVP provided the original concept, broad research directions, and analysis of the results; AT provided the original concept and helped modify the research directions and provided input on the risks of the KD; JL conducted literature searches and organized the manuscript and developed the graphic for the autotoxic loop; MA and HA provided a critical review of the results and wrote sections on brain metabolism.

All authors read and reviewed the final manuscript with critical input.

Competing Interests

The authors have declared that no competing interests exist.

References

  1. Seo JH, Lee YM, Lee JS, Kang HC, Kim HD. Efficacy and tolerability of the ketogenic diet according to lipid: Nonlipid ratios--comparison of 3:1 with 4:1 diet. Epilepsia. 2007; 48: 801-805. [CrossRef]
  2. Martin K, Jackson CF, Levy RG, Cooper PN. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst Rev. 2016; 2: Cd001903. [CrossRef]
  3. Freeman JM, Kossoff EH. Ketosis and the ketogenic diet, 2010: Advances in treating epilepsy and other disorders. Adv Pediatrics. 2010; 57: 315-329. [CrossRef]
  4. Tellez-Zenteno JF, Patten SB, Jette N, Williams J, Wiebe S. Psychiatric comorbidity in epilepsy: A population-based analysis. Epilepsia. 2007; 48: 2336-2344. [CrossRef]
  5. Bostock EC, Kirkby KC, Taylor BV. The current status of the ketogenic diet in psychiatry. Front Psychiatry. 2017; 8: 43. [CrossRef]
  6. Wlodarczyk A, Wiglusz M, Cubala W. Ketogenic diet for schizophrenia: Nutritional approach to antipsychotic treatment. Med Hypotheses. 2018; 118: 74-77. [CrossRef]
  7. Hartman A, Gasior M, Vining E, Rogawski M. The neuropharmacology of the ketogenic diet. Pediatric Neurol Briefs. 2007; 36: 281-292. [CrossRef]
  8. Lutas A, Yellen G. The ketogenic diet: Metabolic influence on brain excitability and epilepsy. Trend Neurosci. 2013; 36: 32-40. [CrossRef]
  9. Atwell D, Laughlin S. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab. 2001; 21: 1133-1145. [CrossRef]
  10. Peters A, Schweiger U, Pellerin L, Hubold C, Oltmanns K, Contrad M, et al. The selfish brain: Competition for energy resources. Neurosci Biobehav Rev. 2004; 28: 143-180. [CrossRef]
  11. Likhodii SS, Serbanescu I, Cortez MA, Murphy P, Snead OC, 3rd, Burnham WM. Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet. Ann Neurol. 2003; 54: 219-226. [CrossRef]
  12. Morris G, Berk M. The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med. 2015; 13: 68. [CrossRef]
  13. Villa RF, Ferrari F, Bagini L, Gorini A, Brunello N, Tascedda F. Mitochondrial energy metabolism of rat hippocampus after treatment with the antidepressants desipramine and fluoxetine. Neuropharmacology. 2017; 121: 30-38. [CrossRef]
  14. Morris G, Maes M. Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab Brain Dis. 2014; 29: 19-36. [CrossRef]
  15. Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J, et al. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain. 2012; 135: 886-899. [CrossRef]
  16. Surace MJ, Block ML. Targeting microglia-mediated neurotoxicity: The potential of NOX2 inhibitors. CMLS. 2012; 69: 2409-2427. [CrossRef]
  17. Prolo C, Alvarez MN, Radi R. Peroxynitrite, a potent macrophage-derived oxidizing cytotoxin to combat invading pathogens. BioFactors (Oxford, England). 2014; 40: 215-225. [CrossRef]
  18. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: How are they linked? Free Radic Biol Med. 2010; 49: 1603-1616. [CrossRef]
  19. Ortiz GG, Pacheco-Moises FP, Bitzer-Quintero OK, Ramirez-Anguiano AC, Flores-Alvarado LJ, Ramirez-Ramirez V, et al. Immunology and oxidative stress in multiple sclerosis: Clinical and basic approach. Clin Dev Immunol. 2013; 2013: 708659. [CrossRef]
  20. Perry VH, Holmes C. Microglial priming in neurodegenerative disease. Nat Rev Neurol. 2014; 10: 217-224. [CrossRef]
  21. Steel CD, Breving K, Tavakoli S, Kim WK, Sanford LD, Ciavarra RP. Role of peripheral immune response in microglia activation and regulation of brain chemokine and proinflammatory cytokine responses induced during VSV encephalitis. J Neuroimmunol. 2014; 267: 50-60. [CrossRef]
  22. Morris G, Maes M. Oxidative and nitrosative stress and immune-inflammatory pathways in patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. 2014; 12: 168-185. [CrossRef]
  23. Morris G, Maes M. A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. Metab Brain Dis. 2013; 28: 523-540. [CrossRef]
  24. Testa F. A pilot study to evaluate tolerability and safety of a modified Atkins diet in ADPKD patients. PharmaNutrition. 2019; v. 9: 2019 v.2019. [CrossRef]
  25. Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure. Circulation. 2007; 116: 434-448. [CrossRef]
  26. Roberts SB, Rosenberg I. Nutrition and aging: Changes in the regulation of energy metabolism with aging. Physiol Rev. 2006; 86: 651-667. [CrossRef]
  27. Waldbaum S, Patel M. Mitochondrial dysfunction and oxidative stress: A contributing link to acquired epilepsy? J Bioenerg Biomembr. 2010; 42: 449-455. [CrossRef]
  28. Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol. 2011; 10: 187-198. [CrossRef]
  29. Seyfried TN, Shelton LM. Cancer as a metabolic disease. Nutr Metab (Lond). 2010; 7: 7. [CrossRef]
  30. Rezin GT, Amboni G, Zugno AI, Quevedo J, Streck EL. Mitochondrial dysfunction and psychiatric disorders. Neurochem Res. 2009; 34: 1021-1029. [CrossRef]
  31. Rossignol DA, Frye RE. Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis. Mol Psychiatry. 2012; 17: 290-314. [CrossRef]
  32. Packer RM, Law TH, Davies E, Zanghi B, Pan Y, Volk HA. Effects of a ketogenic diet on ADHD-like behavior in dogs with idiopathic epilepsy. Epilepsy Behav. 2016; 55: 62-68. [CrossRef]
  33. Stark R, Santos V, Geenen B, Cabral A, Dinan T, Bayliss J, et al. Des-acyl ghrelin and ghrelin O-acyltransferase regulate hypothalamic-pituitary-adrenal axis activiation and anxiety in response to acute stress. Endocrinology. 2016; 157: 3946-2957. [CrossRef]
  34. Marchio M, Roli L, Giordano C, Trenti T, Guerra A, Biagini G. Decreased ghrelin and des-acyl ghrelin plasma levels in patients affected by pharmacoresistant epilepsy and maintained on the ketogenic diet. Clin Nutr. 2019; 38: 954-957. [CrossRef]
  35. Wittekind DA, Kluge M. Ghrelin in psychiatric disorders - A review. Psychoneuroendocrinology. 2015; 52: 176-194. [CrossRef]
  36. Danial N, Hartman A, STafstrom C, Thio L. How does the ketogenic diet work? Four potential mechanisms. J Child Neurol. 2013; 28: 1027-1033. [CrossRef]
  37. Rogawski M, Loscher W, Rho J. Mechanisms of action of antiseizure drugs and the ketogenic diet. Cold Spring Harb Perspect Med. 2016; 6: a022780. [CrossRef]
  38. Dean OM, Turner A, Malhi GS, Ng C, Cotton SM, Dodd S, et al. Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression. Braz J Psychiatry. 2015; 37: 3-12. [CrossRef]
  39. Morris G, Walder K, McGee S, Dean O, Tye S, Maes M, et al. A model of the mitochondrial basis of bipolar disorder. Neurosci Biobehav Rev. 2017; 74: 1-20. [CrossRef]
  40. Bansal Y, Kuhad A. Mitochondrial dysfunction in depression. Curr Neuropharmacol. 2016; 14: 610-618. [CrossRef]
  41. El-Mallakh RS, Paskitti ME. The ketogenic diet may have mood-stabilizing properties. Med Hypotheses. 2001; 57: 724-726. [CrossRef]
  42. Judd LL, Akiskal HS. Depressive episodes and symptoms dominate the longitudinal course of bipolar disorder. Curr Psychiatry Rep. 2003; 5: 417-418. [CrossRef]
  43. Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, et al. Research domain criteria (RDoC): Toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010; 167: 748-751. [CrossRef]
  44. Patrick CJ, Hajcak G. Reshaping clinical science: Introduction to the Special Issue on Psychophysiology and the NIMH Research Domain Criteria (RDoC) initiative. Psychophysiology. 2016; 53: 281-285. [CrossRef]
  45. Heshmati M, Russo SJ. Anhedonia and the brain reward circuitry in depression. Curr Behav Neurosci Rep. 2015; 2: 146-153. [CrossRef]
  46. Lambert C, Da Silva S, Ceniti AK, Rizvi SJ, Foussias G, Kennedy SH. Anhedonia in depression and schizophrenia: A transdiagnostic challenge. CNS Neurosci Ther. 2018; 24: 615-623. [CrossRef]
  47. Cuthbert BN, Kozak MJ. Constructing constructs for psychopathology: The NIMH research domain criteria. J Abnorm Psychol. 2013; 122: 928-937. [CrossRef]
  48. Subramaniapillai M, McIntyre RS. A review of the neurobiology of obesity and the available pharmacotherapies. CNS Spectr. 2017; 22: 29-38. [CrossRef]
  49. Locke AB, Kirst N, Shultz CG. Diagnosis and management of generalized anxiety disorder and panic disorder in adults. Am Fam Physician. 2015; 91: 617-624.
  50. Brandt C, Mula M. Anxiety disorders in people with epilepsy. Epilepsy Behav. 2016; 59: 87-91. [CrossRef]
  51. Kessler R, Perukhova M, Sampson N, Zaslavsky A, Wiitchen H. Twelve-month and llifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012; 21: 169-184. [CrossRef]
  52. Dresler T, Guhn A, Tupak S. Revise the revised? New dimenisons of the neuroanatomical hypothesis of panic disorder. J Neural Transmi. 2013; 120: 3-29. [CrossRef]
  53. Rigoli F, Ewbank M, Dalgleish T, Calder A. Threat visibility modulates the defensive brain circuit underlying fear and anxiety. Neurosci Lett. 2016; 612: 7-13. [CrossRef]
  54. Gomez AF, Barthel AL, Hofmann SG. Comparing the efficacy of benzodiazepines and serotonergic anti-depressants for adults with generalized anxiety disorder: A meta-analytic review. Exp Opin Pharmacother. 2018; 19: 883-894. [CrossRef]
  55. Lader M. Effectiveness of benzodiazepines: Do they work or not? Exp Rev Neurother. 2008; 8: 1189-1191. [CrossRef]
  56. School HM. National Comorbidity Survey (NCS) Boston, MA: Harvard Medical School; 2007. Available from: https://www.hcp.med.harvard.edu/ncs/index.php.
  57. Kessler RC, Chiu WT, Demler O, Merikangas KR, EE W. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005; 62: 617-627. [CrossRef]
  58. Jakubovski E, Johnson JA, Nasir M, Muller-Vahl K, Bloch MH. Systematic review and meta-analysis: Dose-response curve of SSRIs and SNRIs in anxiety disorders. Depress Anxiety. 2019; 36: 198-212. [CrossRef]
  59. Bandelow B, Michaelis S, Wedekind D. Treatment of anxiety disorders. Dialogues Clin Neurosci. 2017; 19: 93-107.
  60. Kessler R, Perukhova M, Sampson N, A Z, H W. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012; 21: 169-184. [CrossRef]
  61. Hasin D, Goodwin R, Stinson F. Epidemiology of major depressive disorder: Results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch Gen Psychiatry. 2005; 62: 1097-1106. [CrossRef]
  62. Lab B. Prevalence and age of onset of bipolar disorders in the general population Athens, Greece: Bipolar Lab; 2018 Available from: https://www.bipolarlab.com/index.php?option=com_content&view=article&id=55:15-prevalence-and-age-of-onset-bipolar-disorders-in-the-general-population&catid=21:bipolar&Itemid=77.
  63. Autism Speaks. CDC increases estimate of autism’s prevalence by 15%, to 1 in 59 children. New York, NY: Autism Speaks; 2018. Available from: https://www.autismspeaks.org/science-news/cdc-increases-estimate-autisms-prevalence-15-percent-1-59-children.
  64. Health NIoM. Trends in prevalence of ADHD Diagnosis among Children 2019. Available from: https://www.nimh.nih.gov/health/statistics/attention-deficit-hyperactivity-disorder-adhd.shtml.
  65. Perälä J, Suvisaari J, Saarni SI, Kuoppasalmi K, Isometsä E, Pirkola S, et al. Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry. 2007; 64: 19-28. [CrossRef]
  66. Baldwin DS, Ajel K. Role of pregabalin in the treatment of generalized anxiety disorder. Neuropsychiatr Dis Treat. 2007; 3: 185-191. [CrossRef]
  67. Pae CU. Pregabalin for treating bipolar mania. Clin Neuropharmacol. 2009; 32: 364. [CrossRef]
  68. Schaffer LC, Schaffer CB, Miller AR, Manley JL, Piekut JA, Nordahl TE. An open trial of pregabalin as an acute and maintenance adjunctive treatment for outpatients with treatment resistant bipolar disorder. J Affect Disord. 2013; 147: 407-410. [CrossRef]
  69. Lydiard RB. The role of GABA in anxiety disorders. J Clin Psychiatry. 2003; 64 Suppl 3: 21-27.
  70. Smith T. Type A gamma-aminobutyric acid (GABAA) receptor subunits and benzodiazepine binding: Significance to clinical syndromes and their treatment. Br J Biomed Sci. 2001; 58: 111-121.
  71. Biagini G, Panuccio G, Avloi M. Neurosteroids and epilepsy. Curr Opin Neurology. 2010; 23: 170-176. [CrossRef]
  72. Wiglusz MS, Landowski J, Michalak L, Cubala WJ. Symptom frequency characteristics of the hamilton depression rating scale of major depressive disorder in epilepsy. Psychiatr Danub. 2015; 27 Suppl 1: S227-230.
  73. Wiglusz MS, Cubala WJ, Galuszko-Wegielnik M, Jakuszkowiak-Wojten K, Landowski J. Mood disorders in epilepsy - diagnostic and methodological considerations. Psychiatr Danub. 2012; 24 Suppl 1: S44-50.
  74. Brietzke E, Mansur RB, Subramaniapillai M, Martinez VB, Vinberg M, Gonzalez-Pinto A, et al. Ketogenic diet as a metabolic therapy for mood disorders: Evidence and developments. Neurosci Biobehav Rev. 2018. [CrossRef]
  75. Maes M, Mihaylova I, Kubera M, Ringel K. Activation of cell-mediated immunity in depression: Association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2012; 36: 169-175. [CrossRef]
  76. Maes M, Lin AH, Delmeire L, Van Gastel A, Kenis G, De Jongh R, et al. Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biolog Psychiatry. 1999; 45: 833-839. [CrossRef]
  77. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biolog Psychiatry. 2010; 67: 446-457. [CrossRef]
  78. Fornaro M, Rocchi G, Escelsior A, Contini P, Martino M. Might different cytokine trends in depressed patients receiving duloxetine indicate differential biological backgrounds. J Affect Disord. 2013; 145: 300-307. [CrossRef]
  79. Galecki P, Szemraj J, Bienkiewicz M, Florkowski A, Galecka E. Lipid peroxidation and antioxidant protection in patients during acute depressive episodes and in remission after fluoxetine treatment. Pharmacol Rep. 2009; 61: 436-447. [CrossRef]
  80. Maes M, De Vos N, Pioli R, Demedts P, Wauters A, Neels H, et al. Lower serum vitamin E concentrations in major depression. Another marker of lowered antioxidant defenses in that illness. J Affect Disord. 2000; 58: 241-246. [CrossRef]
  81. Milaneschi Y, Cesari M, Simonsick EM, Vogelzangs N, Kanaya AM, Yaffe K, et al. Lipid peroxidation and depressed mood in community-dwelling older men and women. PloS one. 2013; 8: e65406. [CrossRef]
  82. Tsuboi H, Shimoi K, Kinae N, Oguni I, Hori R, Kobayashi F. Depressive symptoms are independently correlated with lipid peroxidation in a female population: Comparison with vitamins and carotenoids. J Psychosom Res. 2004; 56: 53-58. [CrossRef]
  83. Czarny P, Kwiatkowski D, Kacperska D, Kawczynska D, Talarowska M, Orzechowska A, et al. Elevated level of DNA damage and impaired repair of oxidative DNA damage in patients with recurrent depressive disorder. Med Sci Monit. 2015; 21: 412-418. [CrossRef]
  84. Yager S, Forlenza MJ, Miller GE. Depression and oxidative damage to lipids. Psychoneuroendocrinology. 2010; 35: 1356-1362. [CrossRef]
  85. Anderson G, Maes M. Oxidative/nitrosative stress and immuno-inflammatory pathways in depression: Treatment implications. Curr Pharm Des. 2014; 20: 3812-3847. [CrossRef]
  86. Eller T, Vasar V, Shlik J, Maron E. Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 445-450. [CrossRef]
  87. Maes M, Ombelet W, De Jongh R, Kenis G, Bosmans E. The inflammatory response following delivery is amplified in women who previously suffered from major depression, suggesting that major depression is accompanied by a sensitization of the inflammatory response system. J Affect Disord. 2001; 63: 85-92. [CrossRef]
  88. Murphy P, Likhodii SS, Nylen K, Burnham W. The antidepressant properties of the ketogenic diet. Biolog Psychiatry. 2004; 56: 981-983. [CrossRef]
  89. Baxter LR, Jr., Phelps ME, Mazziotta JC, Schwartz JM, Gerner RH, Selin CE, et al. Cerebral metabolic rates for glucose in mood disorders. Studies with positron emission tomography and fluorodeoxyglucose F 18. Arch Gen Psychiatry. 1985; 42: 441-447. [CrossRef]
  90. Kramer P, Bressan P. Our (mother's) mitochondria and our mind. Perspect Psychol Sci. 2018; 13: 88-100. [CrossRef]
  91. Kato T, Kato N. Mitochondrial dysfunction in bipolar disorder. Bipolar Disord. 2000; 2: 180-190. [CrossRef]
  92. Cataldo AM, McPhie DL, Lange NT, Punzell S, Elmiligy S, Ye NZ, et al. Abnormalities in mitochondrial structure in cells from patients with bipolar disorder. Am J Pathol. 2010; 177: 575-585. [CrossRef]
  93. Wadee AA, Kuschke RH, Wood LA, Berk M, Ichim L, Maes M. Serological observations in patients suffering from acute manic episodes. Hum Psychopharmacol. 2002; 17: 175-179. [CrossRef]
  94. Munkholm K, Brauner JV, Kessing LV, Vinberg M. Cytokines in bipolar disorder vs. healthy control subjects: A systematic review and meta-analysis. J Psychiatr Res. 2013; 47: 1119-1133. [CrossRef]
  95. Rosenblat JD, Cha DS, Mansur RB, McIntyre RS. Inflamed moods: A review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 53: 23-34. [CrossRef]
  96. Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT. Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol. 2011; 14: 123-130. [CrossRef]
  97. Brown NC, Andreazza AC, Young LT. An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Res. 2014; 218: 61-68. [CrossRef]
  98. Kauer-Sant'Anna M, Kapczinski F, Andreazza AC, Bond DJ, Lam RW, Young LT, et al. Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder. Int J Neuropsychopharmacol. 2009; 12: 447-458. [CrossRef]
  99. Yumru M, Savas HA, Kalenderoglu A, Bulut M, Celik H, Erel O. Oxidative imbalance in bipolar disorder subtypes: A comparative study. Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33: 1070-1074. [CrossRef]
  100. Selek S, Savas HA, Gergerlioglu HS, Bulbul F, Uz E, Yumru M. The course of nitric oxide and superoxide dismutase during treatment of bipolar depressive episode. J Affect Disord. 2008; 107: 89-94. [CrossRef]
  101. Phelps JR, Siemers SV, El-Mallakh RS. The ketogenic diet for type II bipolar disorder. Neurocase. 2013; 19: 423-426. [CrossRef]
  102. Li Q, Zhou JM. The microbiota-gut-brain axis and its potential therapeutic role in autism spectrum disorder. Neuroscience. 2016; 324: 131-139. [CrossRef]
  103. Yang Y, Tian J, Yang B. Targeting gut microbiome: A novel and potential therapy for autism. Life Sci. 2018; 194: 111-119. [CrossRef]
  104. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005; 57: 67-81. [CrossRef]
  105. Grigorenko EL, Han SS, Yrigollen CM, Leng L, Mizue Y, Anderson GM, et al. Macrophage migration inhibitory factor and autism spectrum disorders. Pediatrics. 2008; 122: e438-445. [CrossRef]
  106. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011; 474: 380-384. [CrossRef]
  107. Ziats MN, Rennert OM. Expression profiling of autism candidate genes during human brain development implicates central immune signaling pathways. PloS one. 2011; 6: e24691. [CrossRef]
  108. DeFelice ML, Ruchelli ED, Markowitz JE, Strogatz M, Reddy KP, Kadivar K, et al. Intestinal cytokines in children with pervasive developmental disorders. Am J Gastroenterol. 2003; 98: 1777-1782. [CrossRef]
  109. Ashwood P, Anthony A, Torrente F, Wakefield AJ. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: Mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol. 2004; 24: 664-673. [CrossRef]
  110. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011; 25: 40-45. [CrossRef]
  111. Goines P, Haapanen L, Boyce R, Duncanson P, Braunschweig D, Delwiche L, et al. Autoantibodies to cerebellum in children with autism associate with behavior. Brain Behav Immun. 2011; 25: 514-523. [CrossRef]
  112. Al-Gadani Y, El-Ansary A, Attas O, Al-Ayadhi L. Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children. Clin Biochem. 2009; 42: 1032-1040. [CrossRef]
  113. Rose S, Melnyk S, Trusty TA, Pavliv O, Seidel L, Li J, et al. Intracellular and extracellular redox status and free radical generation in primary immune cells from children with autism. Autism Res Treat. 2012; 2012: 986519. [CrossRef]
  114. Rossignol DA, Frye RE. A review of research trends in physiological abnormalities in autism spectrum disorders: Immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol Psychiatry. 2012; 17: 389-401. [CrossRef]
  115. Giulivi C, Zhang YF, Omanska-Klusek A, Ross-Inta C, Wong S, Hertz-Picciotto I, et al. Mitochondrial dysfunction in autism. JAMA. 2010; 304: 2389-2396. [CrossRef]
  116. Zhang B, Angelidou A, Alysandratos KD, Vasiadi M, Francis K, Asadi S, et al. Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children. J Neuroinflammation. 2010; 7: 80. [CrossRef]
  117. Dhillon S, Hellings JA, Butler MG. Genetics and mitochondrial abnormalities in autism spectrum disorders: A review. Curr Genomics. 2011; 12: 322-332. [CrossRef]
  118. Besag FM. Current controversies in the relationships between autism and epilepsy. Epilepsy Behav. 2015; 47: 143-146. [CrossRef]
  119. Frye RE. Metabolic and mitochondrial disorders associated with epilepsy in children with autism spectrum disorder. Epilepsy Behav. 2015; 47: 147-157. [CrossRef]
  120. Berg AT, Plioplys S, Tuchman R. Risk and correlates of autism spectrum disorder in children with epilepsy: A community-based study. J Child Neurol. 2011; 26: 540-547. [CrossRef]
  121. Tuchman R, Rapin I. Epilepsy in autism. Lancet Neurol. 2002; 1: 352-358. [CrossRef]
  122. Kang JQ, Barnes G. A common susceptibility factor of both autism and epilepsy: Functional deficiency of GABA A receptors. J Autism Dev Disord. 2013; 43: 68-79. [CrossRef]
  123. Cheng N, Rho JM, Masino SA. Metabolic dysfunction underlying autism spectrum disorder and potential treatment approaches. Front Mol Neurosci. 2017; 10: 34. [CrossRef]
  124. Barkley RA. Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD. Psychol Bull. 1997; 121: 65-94. [CrossRef]
  125. Thome-Souza S, Kuczynski E, Assumpcao F, Jr., Rzezak P, Fuentes D, Fiore L, et al. Which factors may play a pivotal role on determining the type of psychiatric disorder in children and adolescents with epilepsy? Epilepsy Behav. 2004; 5: 988-994. [CrossRef]
  126. Vidaurre J, Twanow JDE. Attention deficit hyperactivity disorder and associated cognitive dysfunction in pediatric epilepsy. Semin Pediatr Neurol. 2017; 24: 282-291. [CrossRef]
  127. Pulsifer MB, Gordon JM, Brandt J, Vining EP, Freeman JM. Effects of ketogenic diet on development and behavior: Preliminary report of a prospective study. Dev Med Child Neurol. 2001; 43: 301-306. [CrossRef]
  128. Murphy P, Burnham WM. The ketogenic diet causes a reversible decrease in activity level in Long-Evans rats. Exp Neurol. 2006; 201: 84-89. [CrossRef]
  129. Murphy P, Likhodii SS, Hatamian M, McIntyre Burnham W. Effect of the ketogenic diet on the activity level of Wistar rats. Pediatr Res. 2005; 57: 353-357. [CrossRef]
  130. Debnath M, Berk M. Th17 pathway-mediated immunopathogenesis of schizophrenia: Mechanisms and implications. Schizophr Bull. 2014; 40: 1412-1421. [CrossRef]
  131. Na KS, Jung HY, Kim YK. The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 48: 277-286. [CrossRef]
  132. Rothermundt M, Arolt V, Weitzsch C, Eckhoff D, Kirchner H. Immunological dysfunction in schizophrenia: A systematic approach. Neuropsychobiology. 1998; 37: 186-193. [CrossRef]
  133. Martinez-Cengotitabengoa M, Mac-Dowell KS, Leza JC, Mico JA, Fernandez M, Echevarria E, et al. Cognitive impairment is related to oxidative stress and chemokine levels in first psychotic episodes. Schizophr Res. 2012; 137: 66-72. [CrossRef]
  134. Bitanihirwe BK, Woo TU. Oxidative stress in schizophrenia: An integrated approach. Neurosci Biobehav Rev. 2011; 35: 878-893. [CrossRef]
  135. Davis J, Moylan S, Harvey BH, Maes M, Berk M. Neuroprogression in schizophrenia: Pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry. 2014; 48: 512-529. [CrossRef]
  136. Raffa M, Mechri A, Othman LB, Fendri C, Gaha L, Kerkeni A. Decreased glutathione levels and antioxidant enzyme activities in untreated and treated schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33: 1178-1183. [CrossRef]
  137. Do KQ, Trabesinger AH, Kirsten-Kruger M, Lauer CJ, Dydak U, Hell D, et al. Schizophrenia: Glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci. 2000; 12: 3721-3728. [CrossRef]
  138. Prabakaran S, Wengenroth M, Lockstone HE, Lilley K, Leweke FM, Bahn S. 2-D DIGE analysis of liver and red blood cells provides further evidence for oxidative stress in schizophrenia. J Proteome Res. 2007; 6: 141-149. [CrossRef]
  139. Yao JK, Reddy R, McElhinny LG, van Kammen DP. Reduced status of plasma total antioxidant capacity in schizophrenia. Schizophr Res. 1998; 32: 1-8. [CrossRef]
  140. Reddy R, Keshavan M, Yao JK. Reduced plasma antioxidants in first-episode patients with schizophrenia. Schizophr Res. 2003; 62: 205-212. [CrossRef]
  141. Clay H, Sillivan S, Konradi C. Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci. 2011; 29: 311-324. [CrossRef]
  142. Park C, Park SK. Molecular links between mitochondrial dysfunctions and schizophrenia. Mol Cells. 2012; 33: 105-110. [CrossRef]
  143. Inuwa IM, Peet M, Williams MA. QSAR modeling and transmission electron microscopy stereology of altered mitochondrial ultrastructure of white blood cells in patients diagnosed as schizophrenic and treated with antipsychotic drugs. Biotech Histochem. 2005; 80: 133-137. [CrossRef]
  144. Uranova N, Bonartsev P, Brusov O, Morozova M, Rachmanova V, Orlovskaya D. The ultrastructure of lymphocytes in schizophrenia. World J Biol Psychiatry. 2007; 8: 30-37. [CrossRef]
  145. Nisoli E, Carruba MO. Nitric oxide and mitochondrial biogenesis. J Cell Sci. 2006; 119: 2855-2862. [CrossRef]
  146. Jang B, Han S. Biochemical properties of cytochrome cnitrated by peroxynitrite. Biochimie. 2006; 88: 53-58. [CrossRef]
  147. Batthyany C, Souza JM, Duran R, Cassina A, Cervenansky C, Radi R. Time course and site(s) of cytochrome c tyrosine nitration by peroxynitrite. Biochemistry. 2005; 44: 8038-8046. [CrossRef]
  148. Wlodarczyk A, Szarmach J, Cubala W, Wiglusz M. Benzodiazepines in combination with antipsychotic drugs for schizophrenia: Gaba-ergic targeted therapy. Psychiatr Danub. 2017; 29: 345-348.
  149. McCreadie R. Scottish Schizophrenia Lifestyle Group. Diet, smoking and cardiovascular risk in people with schizophrenia: Descriptive study. Br J Psychiatry. 2003; 183: 534-539. [CrossRef]
  150. Palmer C. Ketogenic diet in the treatment of schizoaffective disorder: Two case studies. Schizophr Res. 2017; 189: 208-209. [CrossRef]
  151. Kraft BD, Westman EC. Schizophrenia, gluten, and low-carbohydrate, ketogenic diets: A case report and review of the literature. Nutr Metab (Lond). 2009; 6: 10. [CrossRef]
  152. Yudkoff M, Daikhin Y, Horyn O, Nissim I, Nissim I. Ketosis and brain handling of glutamate, glutamine, and GABA. Epilepsia. 2008; 49 Suppl 8: 73-75. [CrossRef]
  153. Paoli A, Bianco A, Damiani E, Bosco G. Ketogenic diet in neuromuscular and neurodegenerative diseases. BioMed Res Int. 2014; 2014: 474296. [CrossRef]
  154. Uribarri J, Cai W, Peppa M, Goodman S, Ferrucci L, Striker G, et al. Circulating glycotoxins and dietary advanced glycation endproducts: Two links to inflammatory response, oxidative stress, and aging. J Gerontol A Biol Sci Med Sci. 2007; 62: 427-433. [CrossRef]
  155. Holt EM, Steffen LM, Moran A, Basu S, Steinberger J, Ross JA, et al. Fruit and vegetable consumption and its relation to markers of inflammation and oxidative stress in adolescents. J Am Diet Assoc. 2009; 109: 414-421. [CrossRef]
  156. Kossoff EH, Zupec-Kania BA, Auvin S, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R, et al. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open. 2018; 3: 175-192. [CrossRef]
  157. Sampath A, Kossoff EH, Furth SL, Pyzik PL, Vining EP. Kidney stones and the ketogenic diet: Risk factors and prevention. J Child Neurol. 2007; 22: 375-378. [CrossRef]
  158. Best T, Franz D, Gilbert D, Nelson D, Epstein M. Cardiac complications in pediatric patients on the ketogenic diet. Neurology. 2000; 54: 2328-2330. [CrossRef]
  159. Dehghan M, Mente A, Zhang X, Swaminathan S, Li W, Mohan V, et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): A prospective cohort study. Lancet. 2017; 390: 2050-2062. [CrossRef]
  160. Mente A, Dehghan M, Rangarajan S, McQueen M, Dagenais G, Wielgosz A, et al. Association of dietary nutrients with blood lipids and blood pressure in 18 countries: A cross-sectional analysis from the PURE study. Lancet Diabetes Endocrinol. 2017; 5: 774-787. [CrossRef]
  161. Seidelmann SB, Claggett B, Cheng S, Henglin M, Shah A, Steffen LM, et al. Dietary carbohydrate intake and mortality: A prospective cohort study and meta-analysis. Lancet Public Health. 2018; 3: e419-e428. [CrossRef]
  162. Santos FL, Esteves SS, da Costa Pereira A, Yancy WS, Jr., Nunes JP. Systematic review and meta-analysis of clinical trials of the effects of low carbohydrate diets on cardiovascular risk factors. Obes Rev. 2012; 13: 1048-1066. [CrossRef]
  163. Taylor MK, Sullivan DK, Mahnken JD, Burns JM, Swerdlow RH. Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer's disease. Alzheimers Dement (N Y). 2018; 4: 28-36. [CrossRef]
  164. Arya R, Peariso K, Gainza-Lein M, Harvey J, Bergin A, Brenton JN, et al. Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus. Epilepsy Res. 2018; 144: 1-6. [CrossRef]
  165. Rizvi SJ, Grima E, Tan M, Rotzinger S, Lin P, McIntyre RS, et al. Treatment-resistant depression in primary care across Canada. Can J Psychiatry. 2014; 59: 349-357. [CrossRef]
  166. Uher R, Mors O, Hauser J, Rietschel M, Maier W, Kozel D, et al. Body weight as a predictor of antidepressant efficacy in the GENDEP project. J Affect Disord. 2009; 118: 147-154. [CrossRef]
  167. Pinto JV, Passos IC, Librenza-Garcia D, Marcon G, Schneider MA, Conte JH, et al. Neuron-glia interaction as a possible pathophysiological mechanism of bipolar disorder. Curr Neuropharmacol. 2018; 16: 519-532. [CrossRef]
  168. Raison CL. The promise and limitations of anti-inflammatory agents for the treatment of major depressive disorder. Curr Top Behav Neurosci. 2017; 31: 287-302. [CrossRef]
  169. Shariq AS, Brietzke E, Rosenblat JD, Barendra V, Pan Z, McIntyre RS. Targeting cytokines in reduction of depressive symptoms: A comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry. 2018; 83: 86-91. [CrossRef]
Newsletter
Download PDF Download Citation
0 0
Newsletter  

TOP