One in 6 people suffer from clinical depression. Antidepressants are a first-line
treatment for depression, but at least 1 in 3 patients with depression do not respond to
antidepressants and not everyone responds to, or wants psychological therapy.
Furthermore, there is still a high relapse rate after psychological treatment. Longer
depressive episodes, a higher number of hospitalisations, moderate to high suicide risk,
physical and psychiatric comorbidities, and higher dosage of medication, were partly
explained by the low response (16-17%) and remission rates (13%). Hence, new treatment
options for treatment resistant depression (TRD) are needed.
Recent research in depression indicates that the imbalance between excitatory (e.g.
glutamatergic system) and inhibitory (e.g. GABA system) systems may be a better way of
understanding depression. There is strong evidence that GABAergic neurotransmission is
disrupted in depression and concentrations of GABA are significantly reduced, especially
in treatment-resistant depression. This suggests increasing inhibitory neurotransmitters
(e.g. GABA) could be an alternative way to treat depression.
KDs (ketogenic diets), characterised by high-fat and very low-carbohydrate intake, have
been recently suggested as a possible intervention for depression due to the influence on
neurotransmitters. KDs increase production of the inhibitory neurotransmitter GABA, and
restore microglial activation and neuronal excitability in the lateral habenula, a region
involved in negative reward processing. Furthermore, the mechanisms of action of KD
appear to include several additional potential mechanisms of action in depression
including cellular bioenergetics, reduced oxidative stress, improved brain vascularity,
and influence on the HPA axis (via lowered cortisol), and changes in gut microbiome.
Despite several plausible beneficial effects and increased public interest and rapid
market growth of KD food products (estimated $12.4 billion by 2024), and evidence of
biological plausibility demonstrated in epilepsy and animal models, the efficacy of KDs
for treatment-resistant depression has not yet been established. To our knowledge, there
are only three registered clinical trials underway testing KD for mental disorders,
however, none examine efficacy of KD for treatment-resistant depression and there are no
currently published results. A recent systematic review is the first to appraise the
literature on KD for mental disorders in human samples and highlights the paucity of
robust research. Twelve studies examining 388 participants (9 case reports, 2 cohort
studies, and one observational study) met inclusion criteria and found no high-quality
evidence of KD efficacy for mental disorders. The absence of controlled trials, heavy
reliance on individual case studies, grouping of various clinical disorders together,
lack of uniform definition of KD across studies, including five studies not reporting KD
nutritional intake, and no measurement of ketosis in half the studies make interpretation
of the literature difficult. However, the review data suggest that people with various
mental illnesses who follow a KD can have marked improvements in mental health. Moreover,
a recent review suggests that symptom scales such as the PHQ-9 may be useful but should
be better combined with measures of functioning and quality of life to fulfil patients'
perspectives.
The current study proposes to test whether a 6-week ketogenic diet is an effective
treatment for treatment-resistant depression. Recruitment of 100 participants with
treatment-resistant depression based on a sample size calculation will be conducted. A
5-point difference in PHQ-9 will be considered to represent a clinically important
difference based on prior research. This study reported that the Standard Deviation (SD)
of the change in PHQ-9 over 3 months as 5.8 and as 6.1 over 6 months. Assuming an SD of 6
over 6 weeks would suggest a standardised effect size of 0.83 in PHQ-9 to be clinically
relevant. The sample size to test differences between groups at 90% power and at a type
one error rate of 5% would be 64 (32 per group). A sample size of 100 participants will
be recruited to make the study robust against up to 35% attrition/missing data. In
simulations, it has been confirmed that this sample size remains robust under scenarios
such as unequal sizes of the strata used in minimisation.
After all baseline assessments are complete, participants will be allocated by
minimisation 1:1 to the KD group or control group. A researcher will embed a
non-deterministic algorithm in the Redcap database. This algorithm aims to produce
treatment groups balanced for important prognostic factors by minimising on the following
variables (as below). Only after eligibility and consent is confirmed will the database
reveal the allocation. Investigators delivering the intervention will not be blinded, but
the outcome is collected blind (by self-report), and those involved in analysing the
outcome data will be blinded to allocation.
All follow-up is done online and without trial staff and will therefore not be subject to
observation bias.
Following randomisation, participants will be given information and advice for their
respective group. The KD group involves 6-week pre-prepared ketogenic diet with weekly
KD-focused behavioural and nutritional counselling. The control group will receive weekly
nutritional counselling to increase vegetable consumption and reduce saturated fat
intake. Participants in the control group will receive food vouchers to help purchase
these items. This aims to be a plausible placebo dietary treatment for depression. Usual
treatment for depression will continue, and leaflet material is provided in both groups.
Psychometric questionnaires and biological outcomes will be assessed pre-post
intervention, and at 12-week follow-up, to investigate changes in depression symptom
severity and potential mechanistic pathways.
Initial descriptive statistics will present the profile of the subjects by study arm
without using statistical comparisons. For the primary hypothesis, the change in PHQ-9
scores from baseline to week 6 will be compared between groups. A mixed effect model that
includes treatment group, time and their interaction as fixed effects, and individual
subjects as random effects will be fit using PHQ-9 at all available assessments. A linear
contrast will be used to test the difference between groups in changes from baseline to
week 6 in PHQ-9 scores. Two tailed tests and significance level of 0.05 will be used.
Secondary outcomes will be analysed using analogous mixed effects generalised linear
models. Pre-specified subgroup analyses of the primary outcome will be explored by
baseline depression severity (severe versus moderate) and duration of depression at
baseline split at the median. An exploratory mediation analysis using previously
validated methods to examine whether adherence to the diet, changes in microbiome, and
cortisol awakening response appear to mediate changes in depression. Spearman
correlations will determine associations between alpha diversity metrics, individual
microbes, and PHQ-9 scores. Kruskal-Wallis one-way analysis of variance tests will be
performed to compare relative abundance of the top ten genera, with false discovery rate
(FDR) corrections between dietary groups. Complete case analysis will be used as the
primary analysis if the proportion of missing data is below 5%. A sensitivity analysis to
explore reasons for missingness and determine appropriate handling of missing data will
be conducted.
A 12-member advisory panel of adults with lived experience of mental and physical illness
(50% from ethnic minority backgrounds) in collaboration with The McPin Foundation has
been formed to inform all stages of this research trial. Members have expressed interest
to know whether KDs can treat depression, and they welcome this kind of research. An
additional 8 members of the public who have depression, of whom 3 had previously followed
a KD diet were involved in the study design (e.g. social media and public advertising to
engage participants, prepared meals preferred, motivational messages, strategies aimed at
addressing relapsing and relapse following KD diets) before ethics submission.
Participants in the trial will be offered the opportunity to hear the results of the
study upon completion, and a lay summary and infographic will be provided.
A six-member trial steering committee (TSC) has been formed to provide independent
oversight of the trial. Three independent members (50%) whose scientific, psychiatric,
and statistical expertise is directly relevant to the trial, have verified they have no
relationship to the investigators, the trial funders, nor employed by the same
institution. The TSC will meet at least annually at appropriate time-points to ensure the
trial is conducted in accordance with clinical trial standards.
There are few established and widely available treatments available for people with TRD.
This is the first randomised, controlled trial assessing the effects of KDs on symptoms
of depression in patients with TRD. Findings from this trial will provide evidence of
efficacy of a new option for alleviating depressive symptoms in people who do not respond
to antidepressants. If the treatment proves efficacious, it will create a potential new
way to treat these patients.