THE KETOGENIC DIET FOR REFRACTORY MENTAL ILLNESS: A RETROSPECTIVE ANALYSIS OF 31 INPATIENTS

Albert Danan>1, Eric C. Westman2, Laura R. Saslow3, and Georgia Ede4*

^{1 Faculty of Medicine Rangueil, University of Toulouse, Toulouse, France
2 Department of Medicine, Duke University Medical Center, Durham, NC, United States
3 Department of Behavior and Biological Health Sciences, School of Nursing, University of Michigan, Ann Arbor, MI, United States
4 Independent Researcher, Northampton, MA, United States}

Background and Assumptions: Robust evidence supporting the therapeutic benefit of ketogenic diets in epilepsy and other neurological conditions suggests that this same metabolic approach may also benefit psychiatric conditions.

Studio design: In this retrospective clinical care analysis, 31 adults with severe and persistent mental disorders (major depressive disorder, bipolar disorder, and schizoaffective disorder) whose symptoms were poorly controlled despite intensive psychiatric management, were admitted to a psychiatric hospital and placed on a ketogenic diet limited to a maximum of 20 grams of carbohydrates per day as a support to conventional hospital care. The duration of the intervention varied from 6 to 248 days.

Results of the Study: Three patients were unable to follow the diet for >14 days and were excluded from the final analysis. Among the included participants, mean and standard deviations (SD) improved for Hamilton Depression Rating Scale scores from 25.4 (6.3) to 7.7 (4.2), P < 0.001 and Montgomery-Åsberg Depression Rating Scale scores from 29.6 (7.8) to 10.1 (6.5), P < 0.001. Among the 10 patients with schizoaffective disorder, the mean (SD) of Positive and Negative Symptom Scale (PANSS) scores improved from 91.4 (15.3) to 49.3 (6.9), P < 0.001. Significant improvements were also observed in metabolic health measures, including weight, blood pressure, blood glucose, and triglycerides.

Conclusions: Administration of a ketogenic diet in this semi-controlled setting to patients with mental disorders refractory to treatment was feasible, well tolerated, and associated with significant and substantial improvements in symptoms of depression and psychosis and in multiple indicators of metabolic health.

At this link the original text of the study in English

INTRODUCTION: Globally, an estimated 85 million people suffer from severe and persistent bipolar and psychotic mood disorders, and at least 280 million have depressive disorders. However, even among those who have access to modern professional treatment, many fail to achieve significant improvement and remission is rare. Nearly half of those receiving treatment for bipolar disorder continue to experience recurrent mood episodes. In Europe, about 19% of those with depression are considered “treatment resistant.” Globally, only 23% of those with schizophrenia respond well to antipsychotic medications, with symptom relief often achieved at the expense of quality and length of life. Metabolic disorders such as hyperglycemia, hypertriglyceridemia, and weight gain are common in those with bipolar disorder and those with schizophrenia, significantly increasing the risk of obesity, type 2 diabetes, cardiovascular disease, and other chronic health conditions. In fact, nearly two-thirds of patients initially hospitalized with acute psychosis develop obesity within 20 years of follow-up. Metabolic and other side effects lead about 74% of people to stop taking antipsychotic drugs within 18 months, contributing to high rates of hospitalization and relapse.

These profound limitations of psychopharmacological treatments make the search for new approaches to mental illness of paramount importance. One interesting intervention attracting increasing attention in recent years is the ketogenic diet (KD), which restricts carbohydrates and induces lipolysis, generating circulating ketone bodies that serve as an additional source of fuel for the brain, reducing its dependence on glucose.

Although the study of KD for the treatment of psychiatric diseases is still in its infancy, the implementation of KD in neurological diseases dates back a century when it proved useful in the management of epilepsy. The robust evidence base that now supports the application of KD to epilepsy and a growing number of other challenging neurological conditions suggests that this same metabolic approach may also be beneficial for psychiatric conditions. For example, it is well established that epilepsy and bipolar disorder share many neurochemical bases, and this overlap is supported clinically by the fact that many of the same molecules prescribed to control seizures are also prescribed to stabilize mood. In fact, the dividing line between brain diseases considered to be neurological in nature and those considered to be psychiatric in nature may be more rhetorical than biological, since both categories of diseases originate in the same organ and show many biochemical similarities, including dysregulation of neurotransmitter systems, destabilization of neural networks, neuroinflammation, excessive oxidative stress, impairment of neuroplasticity, mitochondrial dysfunction, and disruption of cerebral glucose metabolism.

However, because rigorous evidence from clinical trials in this field is not yet available, it is still unclear to what extent severe mental disorders can benefit from a metabolic approach. Therefore, to the isolated case reports of individuals with major depressive disorder, bipolar disorder and psychotic disorder who have benefited from a KD, we add this case series of 31 patients with treatment-resistant mental disorders treated with a KD in a semi-controlled hospital setting.

BACKGROUND

Dr. Danan, first author of the study, has been a practicing psychiatrist in Toulouse, France, for 35 years. The population he serves consists mainly of people of French and North African descent with severe persistent mental disorders, many of whom also suffer from metabolic diseases such as obesity, hypertension, and type 2 diabetes. Despite intensive outpatient management with psychotropic drugs and psychotherapy, most of these individuals require frequent hospitalization and are unable to work due to psychiatric disability. After observing significant improvement in drug-refractory seizures and autistic behaviors in a family member within a few weeks of adopting a KD, Dr. Danan became interested in the potential of KD to improve the psychiatric and metabolic status of his most treatment-resistant patients, regardless of diagnosis. He created a psychiatric metabolic treatment program within the Clinique du Castelviel, a 129-bed general psychiatric hospital in Castelmarou, France, where patients with chronic mental illnesses who had exhausted standard psychiatric therapies could try a KD in a supportive environment and supervised by medical staff.

MATERIALS AND METHODS

This is a retrospective analysis of adults admitted with severe and persistent mental disorders who were administered a KD instead of the standard hospital menu. Between May 2019 and April 2020, 31 adults whose chronic psychiatric symptoms were poorly controlled despite intensive management with psychotropic drugs were admitted to the Clinique du Castelviel and underwent a KD under the supervision of their treating psychiatrist, Dr. Danan. This treatment program was approved by the Clinique du Castelviel administration and ethics review.

Participants

The participants were unpaid volunteers selected by Dr. Danan from his psychiatric practice
outpatient. Informed consent was obtained in each case. The eligibility criteria were the
Failure to improve adequately with conventional psychiatric care and willingness to try
a KD. Exclusion criteria were anorexia nervosa, a BMI less than 18.5 kg/m2, and pregnancy,
breastfeeding and contraindicated medical conditions (23). The primary psychiatric diagnoses
were bipolar disorder type two (n = 13), schizoaffective disorder (n = 12) and disorder
major depressive disorder (n = 7). All participants had at least one indicator of poor state of
metabolic health, such as overweight, obesity, hypertension, and/or elevated fasting blood sugar. The
Most of the participants had been followed by Dr. Danan for many years (mean [SD] 10 [7] years, range 5 months to 30 years), and all had been previously hospitalized in the field
psychiatrist under his supervision one or more times, either at the same facility or at a
similar affiliated facility, with minimal clinical improvements. None of the participants had ever
Attempted to follow a low-carbohydrate diet previously.

Of the 31 patients, 22 were admitted voluntarily with the aim of initiating KD in a setting
monitored. The remaining 9 were initially admitted for conventional care, but
They later accepted KD because nondietary therapies proved ineffective.
All 31 were taking psychotropic drugs at the time of KD onset.

In addition to the KD protocol, which was the foundation of their treatment plan, participants have
also received the usual care available to all patients admitted to this unit. The staff
hospital consisted of 8 psychiatrists, 3 psychologists, 2 general practitioners, 2 social workers, a
occupational therapist, an exercise instructor, and a dietitian. Diseases typically treated
at this facility included mood disorders, schizophrenia, substance use disorders, and
eating disorders. Participants resided in the inpatient unit 6 days a week.
but they were free to leave the hospital over the weekend for up to 36 consecutive hours.

Statistical analysis

The means and standard deviations were calculated for continuous variables; the distributions of
frequency were calculated for nominal and ordinal variables. Paired t tests were used
when the pre-post differences had a normal distribution and rank tests with sign of
Wilcoxon when the differences were asymmetric, using SPSS 28.0.1.1.

Interventions

The KD protocol employed was adapted from that used by Dr. Westman in clinical trials at
Duke University (24); see Supplementary Figure 1: Protocol of the ketogenic diet for the
details and an example of a meal plan. In short, carbohydrate intake was limited to a
maximum of 20 grams total per day (about 5% of daily calories), exclusively from
vegetables, nuts, lemon juice, and small amounts of dark chocolate. Protein constituted the
15-20% of daily calories and came from meat, fish, poultry, dairy products, eggs and nuts. The fats
constituted 75-80% of the diet; permitted added fats were olive oil, coconut oil, butter,
Mayonnaise and sour cream.

Participants were provided 3 meals per day in accordance with the protocol (prepared by the dietician
of the hospital to ensure sufficient protein and calories), 1 box of snacks per day
protocol-compliant (formulated by Dr. Danan, purchased by participants, and dispensed
daily by Dr. Danan) and a list of approved foods to follow at all times. I
participants also received daily fish oil supplementation (250 mg: 18%
EPA, 12% DHA), magnesium oxide (300 mg), copper (1 mg), vitamin B1 (1.1 mg), vitamin B5 (6 mg),
vitamin B6 (3.4 mg), vitamin B12 (2.5 mg) and vitamin C (330 mg).

Dr. Danan met individually with each participant 6 days a week
to monitor clinical progress and provide dietary education and support. Dietary adherence is
was estimated using information gathered from these frequent interviews with the physician, the diaries
participants' daily food intake and the nursing staff's observations. Adherence is
has been characterized as excellent for those who have successfully restricted the intake of
carbohydrates to a maximum of 20 grams per day at least 6 days a week, good for those
who have achieved this goal at least 5 days a week and sufficient for those who
achieved this goal at least 4 days a week. Urinary acetacetate was
measured at least once for each participant during the intervention period. The monitoring
metabolism, including blood tests, blood pressure, and body weight, was
Performed on day 0 of KD and again on the final day of KD, just before discharge
hospital.

Date of admission, length of hospitalization, length of KD, and other non-dietary aspects of care
varied according to clinical circumstances. Medical therapies were adjusted according to the
clinical judgment

Main outcome measures

The main outcome measures established before the intervention were change in symptoms
depression as measured by the Hamilton Depression Rating Scale (HAM-D) (25) and the
Montgomery-Åsberg Depression Rating Scale (MADRS) (26), and the change in the
psychotic symptoms as measured by the Positive and Negative Symptom Scale (PANSS) (27, 28).

Secondary outcomes of interest include medical and psychiatric safety, effect on biomarkers
metabolism, changing drug treatment needs, and changing
severity of the disease, assessed using the Clinical Global Impressions Scale (CGI-S) (29, 30).

RESULTS

Characteristics of patients

Three of the 31 patients (10%) were unable to follow a KD for more than 14 days and were
excluded from the final analysis due to lack of outcome data; this case series is therefore
consisting of 28 hospitalized adults [mean (SD) age, 50 (11.3) years, range 27-73 years; 71% women].
The mean duration (SD) of hospitalization was 85.4 (76.8) days (range 16-270 days)
and the mean duration (SD) of KD was 59.1 (49.6) days (range 15-248 days).

Dietary adherence

Regarding the 3 excluded patients mentioned above: 1 discontinued KD citing aversion to the
food fats, 1 cited lack of family and financial support, and 1 cited difficulties
financial, food fat aversion and disapproval of the restrictiveness of the plan.
Among the 28 included patients who followed the diet for more than 2 weeks, measurements of ketone
in urine were obtained once during surgery and were positive in 18 of 28 patients
(64%). Dietary adherence was characterized as excellent in 11 patients (39%), good in 12
patients (43%) and sufficient in 5 patients (18%).

The changes in mental health measures described below are presented in Table 1.
Clear improvements in mood and psychotic symptoms were observed in all 28 patients
(100%) during the intervention, typically within 3 weeks or less of KD initiation.

Symptoms of schizophrenia

After the KD intervention, all 10 (100%) patients with a primary diagnosis of disorder
schizoaffective showed improvement in PANSS scores, with the mean score (SD)
of PANSS that decreased from 91.4 (15.3) to 49.3 (6.9), P < 0.001, Cohen's d = 3.5. A reduction of 16.5 or
more points in the PANSS score is considered the minimum clinically important difference (31) and is
was achieved in 10/10 (100%) of the patients.

HAM-D was administered to 23 of 28 patients, including all 18 with a primary diagnosis of
non-psychotic illness. After KD intervention, all 23 (100%) patients showed a
Improvement in HAM-D scores, with the mean (SD) HAM-D score dropping from 25.4
(6.3) to 7.7 (4.2), P < 0.001, Cohen's d = 3.1. The MADRS was administered to 21 of the 28 patients,
including all 18 with a primary diagnosis of nonpsychotic illness. After the KD intervention,
all 21 (100%) showed improvement in MADRS scores, with the mean score
(SD) of MADRS that decreased from 29.6 (7.8) to 10.1 (6.5), P < 0.001, Cohen's d = 3.6.

A reduction of at least 4 points in HAM-D is considered the minimum difference clinically
important and was achieved by all 22 patients whose HAM-D scores were assessed,
regardless of diagnosis. A reduction of at least 7 points, considered clinically
significantly important, was achieved by 21/22 patients (95%) (32).

A reduction of at least 6 points in MADRS is considered the minimum difference clinically
important and was achieved by all 21 patients (100%) whose scores were assessed
MADRS, regardless of diagnosis.

CGI-S

Disease severity was assessed in 27 of the 28 patients using the CGI-S. After surgery
of the KD, the mean CGI-S (SD) improved from 4.9 (1.2) to 2.0 (1.1), Cohen's d = 3.8. Since this
change violated the assumption of normality, we conducted a Wilcoxon test with ranks
with signs that indicated that the change was statistically significantly different, Z =
-4.65, P < 0.001 (see Figure 1), with 12 of 28 patients (43%) achieving remission
clinical. A reduction of 1 point in the CGI-S is considered the minimal difference clinically
important (33). All patients achieved a reduction of at least 2 points in the CGI-S,
regardless of diagnosis (Cohen's d = 3.8).

Changes in drug therapy

Before the intervention, the average number (SD) of psychotropic drugs taken per patient was 5.3 (2.0) with 25
of 28 (89%) patients who were taking at least one antipsychotic medication. At the end of the intervention, the
number and/or dosage of psychotropic medications had been reduced in 18 of 28 (64%) patients (cf.
Figure 2). Among the 7 patients who were also taking nonpsychotropic drugs, the number and/or dosage
of these drugs was reduced in 5 of 7 patients (71%). Somatic medications reduced and/or discontinued
included insulin, metformin, atorvastatin, gliclazide and ticagrelor.

Measures of metabolic health

Measures of metabolic health are detailed in Table 2. Before the intervention, weight
mean body size (SD) was 198.5 (42.1) pounds (range 145.7-310.9 pounds) and the mean BMI (SD) was
of 31.9 (6.7) kg/m2 (range 23.0-51.2 kg/m2). The initial BMI was in the normal range (18.5-
24.9 kg/m2) for 3/28 (10.7%) patients, in the overweight range (25.0-29.9 kg/m2) for 7/28 (25.0%)
patients and in the obese range (≥30.0 kg/m2) for 18/28 (64.3%) patients. At the conclusion
of the intervention, all but one patient (27 of 28; 96.4%) had lost weight. It should be noted that 24 of
25 (96%) patients taking antipsychotic drugs lost weight, and 12 of these 25 (48%)
Have achieved clinically significant weight loss [defined as weight reduction
body ≥5% (34)]. Overall, the weight change [mean (SD), -10.8 (-7.1) lbs] and the
change in BMI [mean (SD), -1.7 (1.2) kg/m2] were both significant (P 150 mg/dl), significant reductions of 100 mg/dl or more were observed
in 7 (50%), with 5 patients (36%) no longer meeting criteria for hypertriglyceridemia after
intervention. C-reactive protein levels were measured but due to several infections, the values
were considered unreliable.

Tolerability of the ketogenic diet

Most patients initially experienced one or more commonly reported symptoms
during early adaptation to ketogenic diet (35), such as headache, insomnia, irritability,
arousal, dizziness and carbohydrate cravings. These symptoms were mild, requiring no
special medical or psychiatric management and resolved within 2 weeks or less. Beyond this
initial transition period, KD was well tolerated psychiatrically by all the
patients, and 27 of 31 (87%) had no problematic somatic side effects. Two patients
(excluded) cited fat intolerance, and 2 (included) had diarrhea and/or vomiting that was
resolved within 4 weeks. A fifth patient developed gastroenteritis during week 5
of the surgery and discontinued the diet, but subsequently resumed KD with no adverse effects,
suggesting that gastroenteritis was unlikely to be related to KD.

Post-hospitalization dietary adherence

In the months following hospital discharge, 13 of the 28 included patients (46%) reported
adequate adherence to KD at home, 5 (18%) reported partial adherence, 6 (21%) had
discontinued the diet, 1 discontinued and then resumed it, and 3 were lost to follow-up. Those who have
chose to continue KD after discharge did so to maintain or improve benefits
psychiatric and metabolic conditions experienced during hospitalization. The reasons for the discontinuation
include cost, difficulty in meal preparation, restrictiveness and lack of motivation.

DISCUSSION

This iteration of KD was safe, feasible to administer in a hospital setting, well
tolerated by most patients and associated with substantial improvements and statistically
significant in symptoms of depression and psychosis not observed during previous hospitalizations.
Effect sizes were large (Cohen's d > 0.8) (36) on all measures of health outcomes
mental in all subgroups and very large among those with a primary diagnosis of depression
major. Since the therapies implemented during this hospitalization differed only by
the addition of KD to usual care, we consider it likely that KD contributed
considerably to these unprecedented improvements in mental health, particularly in the
79% of patients whose psychotropic medications were reduced or not changed. The remarkable
improvements in several metabolic health indicators, including body weight, blood pressure
arterial, blood glucose, and triglycerides observed in this series would be difficult to attribute to any
other aspect of hospitalization other than KD, which is known to facilitate these changes
healthy (37).

Historical and scientific context

A recent nonrandomized study of 262 outpatients with type 2 diabetes treated with
a KD found significant improvement in mood. This cohort included 36 patients
With mild clinical depression, more than half of whom no longer met the criteria for depression
to week 10 (38).

To the best of our knowledge, this case series represents the first exploration of the use of the
KD in hospitalized patients with bipolar disorder or severe depression and only the second exploration
of the use of KD in hospitalized patients with psychotic disorder, the first published in 1965 (39).
In that pilot study, a KD was administered to 10 women with schizophrenia refractory to the
treatment, with statistically significant improvements in mean symptom scores after 2
weeks. Since then, several isolated cases have been documented describing people with diseases
mentals that have benefited significantly from KDs; the first of these was published by one of
us in 2009 (40) and offers an example of long-term resolution of psychotic symptoms and the ability
To stop antipsychotic therapy completely.

Biological plausibility

Biological plausibility that KDs may be of therapeutic benefit in depression
major, in bipolar disorder and schizophrenia is strongly supported by the literature
science (18:41-44).

Major Depression

Inflammation is implicated in all three conditions, but has been studied in more detail
In depression. Inflammation plays a role in the development and course of many cases of
clinical depression and is associated with poor response to antidepressant drugs (45, 46). KD is
been shown to reduce inflammation through complex effects on both pathways
central and peripheral immunoregulatory systems (47-50). KD also affects many systems
neurotransmitters involved in depression, including dopaminergic, serotonergic systems,
glutamatergic and GABAergic (51).

Bipolar Disorder

Among those with bipolar disorder, there is a higher prevalence of metabolic dysfunction of the
glucose even in drug-naïve individuals (52). Calkin (53) found that those with resistant
to insulin or type 2 diabetes are more likely to experience rapid mood cycles, less likely to
respond to lithium and more prone to undergo a more progressive course of disease. The proposed mechanisms
through which glucose and insulin dysregulation can affect mood include the
oxidative stress damage, which, in turn, could impair mitochondrial function (16).
Napolitano et al. (54) recently found that KD can increase brain levels of
glutathione, a ubiquitous intracellular antioxidant key to buffering oxidative stress.
Campbell and Campbell (55) speculate that KD may help improve the symptoms of the disorder
bipolar by shifting the brain's primary source of fuel from carbohydrates to ketone bodies, preventing
thus existing mitochondrial defects and reducing further mitochondrial injury. Calkin et al. (56) have
proposed that insulin resistance through inflammatory damage to endothelial cells,
can compromise the integrity of the blood-brain barrier (BBB) in people with
bipolar disorder. Interestingly, disruption of tight junctions critical to the
structure and function of the BBB has been observed not only in bipolar disorder, but also in the
major depression and in schizophrenia (57).

Schizophrenia

Hyperinsulinemia, insulin resistance, and glucose metabolism disorder are more
common in treatment-naïve individuals who experience first-episode psychosis compared with the
general population (58). Although this association alone is not sufficient to support a
causal relationship between metabolic dysregulation and psychotic symptoms, several cases have been reported
Of acute hyperglycemia associated with transient psychotic symptoms in patients with type 1 diabetes and type
2 (59). Pathophysiological features of schizophrenia shown in preclinical studies by Sarnyai et
al. (44) that improve in response to a KD include hypofunction of N-methyl-D-aspartate receptors
(NMDA), sensory gating deficit and glutamate excitotoxicity.

KDs also help rebalance neurotransmitter systems, (16) stabilize neural networks
(60), improve neuroplasticity (61) and bridge the energy gap resulting from hypometabolism of the
brain glucose associated with major depression, bipolar disorder, and schizophrenia (17).

Strengths and limitations

The unique strengths of this series include the diversity of psychiatric diagnoses and the number
relatively large number of patients exposed to the same therapy in the same clinical setting semi-
controlled. It is with these elements in mind that we have chosen not to report these results of the
users as individual case studies. The provision of education, monitoring and support by one
Psychiatrist who had confident therapeutic alliances with his patients before the intervention
seemed to contribute to patients' openness to the intervention and probably improved adherence
dietetics and honesty about transgressions, although this context of special treatment
makes it unclear whether the same results would be possible under different circumstances.

Neither the psychiatrist in charge of outcome assessment nor the patients themselves had been
blinded with respect to the intervention, so there is a risk that impressions of clinical progress may
Have been affected. Although patients may have benefited simply from the fact that the
of having been hospitalized, a strength of this cohort was that all patients had been
previously hospitalized under Dr. Danan's care at least once (and in many cases, more
times) in this same facility or in a sister facility where all aspects of nondietary care
were very similar, however, Dr. Danan reported that he had never observed this degree of
clinical improvement in these patients previously. These patients could therefore be
regarded as their own historical comparison group, even though mental health outcomes do not
Have been formally measured during previous hospitalizations.

As with any intervention in which ad libitum dietary patterns are replaced with a
structured dietary model of interest, multiple dietary variables were manipulated, thus
Even if it were possible to assign clinical benefits to KD, it would still be difficult to determine
What aspect(s) of the KD may be responsible for those benefits. For example, this
iteration of KD was not only low in carbohydrates, but also grain-free, very
low in processed foods and supplemented with micronutrients. Since KD meals and snacks were
portion-controlled, patients may also have consumed fewer calories than usual.

It should also be noted that this context did not allow complete control over the intervention
diet, as participants were allowed to leave the unit on weekends and, while
were in the unit, they could interact with non-participating patients who were served standard food.
Because this was not a metabolic research room, monitoring of ketones in urine (which
may be useful in assessing dietary adherence) was burdensome for the busy staff, and so it was
conducted only once per patient. However, weight loss is another piece of evidence that the
patients adhered to the diet program, as most people who were overweight or
obese will lose weight with a KD (24), and clinically significant weight loss in people
affected by severe mental disorders is otherwise unforeseen, even when they are implemented
Lifestyle therapies aimed at weight loss (62). All but one patient lost weight,
including 96% of those taking antipsychotics, and nearly half achieved a loss of
clinically significant weight [defined as a reduction in body weight ≥5% (34)]. This
positive result alone makes a compelling case for the implementation of KD in people who
take antipsychotic drugs, whether or not they improve psychiatric symptoms in response to KD,
as counteracting antipsychotic-induced weight gain is extremely difficult (63).

Whether weight loss alone could lead to reduced symptoms of depression,
bipolar disorder (64) and/or psychosis remains a largely unanswered question. In
People with type 2 diabetes treated with a KD, the improvement in symptoms of depression did not
is correlated with weight loss (38). While studies find that people with depression
clinic undergoing bariatric surgery report fewer depressive symptoms 6 months or more after
intervention, weight change appears to be an unreliable predictor of improvement
mood (65). We are not aware of any studies evaluating the impact of weight loss alone
On the symptoms of bipolar or psychotic disorders.

Practical considerations

There are ketogenic dietary protocols on a spectrum ranging from the “classic” KD originally
used to treat drug refractory pediatric epilepsy (90% of fat, 6% of protein, 4% of
carbohydrates) to modified KDs that allow higher percentages of protein, to Atkins diets
modified (66), in which protein can be consumed until satiety (67). The protocol chosen
by Dr. Danan to fit his patients falls into the latter category, although the intake of
protein in this context was limited to 15-20% of daily calories at least 6 days to
week. An advantage of this more liberal approach is that precise control is not required
of macronutrient proportions, simplifying the logistics of both administration and
Of the adherence.

In addition to rare metabolic diseases typically diagnosed in childhood, there are several
health conditions considered by many to be absolute contraindications for the initiation of KD in the
adults; these include acute pancreatitis, nephrolithiasis, renal failure, liver failure,
congestive heart failure, anorexia nervosa, and concomitant use of SGLT2 inhibitors.

A well-formulated KD can quickly and effectively lower glucose levels in the
blood, insulin, and blood pressure, all considered clinically desirable goals in many
patients, particularly those with metabolic syndrome. However, these physiological adaptations
generally benefits to KD require careful medication management. Drugs that lower
blood glucose (such as insulin, sulfanilureas, and meglitinides) and drugs that lower the
blood pressure (such as diuretics and ACE inhibitors) require diligent monitoring because they
some may have to be reduced or even discontinued as early as the first day of the start of KD
to minimize the risk of hypoglycemic, hypotensive and hypovolemic events (68, 69).

We are not aware of any published research on possible interactions between diets
ketogenic and psychotropic drugs, with the relevant exception of anticonvulsants. Studies on patients
with epilepsy treated with a KD have found that levels of anticonvulsants can
change in response to diet. Although these changes are typically small and clinically
insignificant, valproate levels can decrease significantly (70). Since these agents
have not yet been formally studied in people with psychiatric conditions, it would be
prudent to monitor blood levels of all anticonvulsants, as well as any other medications
psychiatric conditions for which changes in blood levels may be of clinical importance, such as
lithium. With these known cautions, for most adult patients, the potential benefits of the
Simple, well-formulated KDs would seem to outweigh the potential risks (71).

As the clinical response to KD in this cohort of patients usually occurred within 3
weeks or less, it should be noted that the highly variable and, in some cases, long duration of the
hospitalizations in this cohort was not related to KD, but largely to socioeconomic factors.
In France, inpatient psychiatric care is free for patients, bed availability is
high and hospitalization criteria are liberal, so prolonged stays are common.
Since this iteration of KD was generally well tolerated and safe from the perspective of
psychiatric even in the complex cases that make up this series, hospitalization may not
be necessary as long as adequate medical supervision is provided, especially with regard to
Is about medication management.

The key to a successful transition to a KD in any population is education
dietary and support, probably particularly important in this population was the
Provision of prepared meals and snacks since depression, psychosis and other severe psychiatric symptoms
Would have otherwise made the adoption and adherence to KD (or any other new diet) logistical
formidable. It is conceivable that a carefully designed intensive outpatient program would
can provide the necessary structure and support for patients with serious mental illness to
transition to a KD, and it is encouraging to see that almost half of the patients in this group were able to
To continue following a KD after discharge.

Considerations for future research

Our observations warrant further research into the potential of KD to improve life
Of people with mental illness. Many unanswered questions remain in this
nascent field that carefully designed randomized controlled trials adequately
enhanced, conducted in inpatient, outpatient or virtual settings, could begin to address.
Since serum beta-hydroxybutyrate measurements are currently the most reliable method for
assess metabolic response to KD, daily monitoring of this metric would help the
physicians and patients to understand whether the degree and consistency of ketosis is important for clinical outcomes.

CONCLUSIONS

In this retrospective analysis of clinical care, which to our knowledge represents the largest
number of people with severe mental illness treated with a KD in a hospital setting so far,
we found that KD was feasible, safe, well tolerated, and associated with remarkable improvements
in mental health symptoms and in many metabolic health indicators. Although the following are necessary
More rigorous research to confirm the association between KD and improved health outcomes
mental, these results indicate that medically supervised carbohydrate restriction is a
Simple, safe, and universally accessible intervention worth considering as a strategy
adjunctive in the treatment of severe mood disorders and psychosis.

DATA AVAILABILITY STATEMENT

Raw data supporting the conclusions of this article will be made available by the authors,
Without undue reservation.

ETHICS STATEMENT

This treatment program has been approved by the Administration and Ethics Review
of the Clinique du Castelviel (Castelmarou, France). Patients/participants provided their
Written informed consent to participate in this study.

AUTHOR'S CONTRIBUTIONS

AD designed and implemented the intervention and generated clinical data and observations. GE has
conducted the literature review and wrote the manuscript. EW and LS conducted analyses
statistics. All authors contributed to the article and approved the final version of the
manuscript.

THANKS

We thank AD patients for their willingness to participate in this program and Suzanne
Smith for his help in organizing, formatting and editing the manuscript, as well as for the
Support in translation, data management, and figure creation.

SUPPLEMENTARY MATERIAL

Supplement: Protocol of the Ketogenic Diet

The implemented ketogenic dietary protocol was adapted from the induction phase of Dr. Eric Westman's (1) modified Atkins diet, which limits total carbohydrate intake to 20 grams per day, following the guidelines below. The hospital dietitian used these guidelines to create an eating plan consisting of three meals per day that were served to all participants at least six days per week. The intervention menu differed from the guidelines below in only one important aspect, namely, the amounts of meat, fish, poultry, and eggs were limited rather than consumed at satiety, resulting in a plan with a macronutrient composition of 15-20% protein, 75-80% fat, and 5% carbohydrate.

1. Eat your fill: meat, fish, poultry and eggs, including their natural fats, free of starchy coating [Note: the meal plan used in this intervention limited daily protein intake to 15-20% of total calories].

2. Consume 2 cups of leafy greens daily (measured raw). Allowable vegetables include all leafy green vegetables, arugula, bok choy, cabbage, chives, endive, radishes, spring onions, and watercress. “Cup” is an Anglo-Saxon unit of measurement “cup.” A cup does not have a fixed value in grams for vegetables, but varies according to the type of vegetable and its density, since the “cup” is a unit of volume. There are measuring cups 1 cup, 1/2 cup, etc. such as these.

3. Consume 1 cup of cooked vegetables daily (measured cooked). Allowable vegetables include artichokes, asparagus, broccoli, Brussels sprouts, cauliflower, celery, cucumbers, eggplant, green beans, icebergs, leeks, mushrooms, okra, olives, onions, peppers, squash, scallions, peas, bean sprouts, light sprouts, peas, zucchini, tomatoes, rhubarb, and green beans.

4. Foods allowed as snacks: pate, ham, chorizo, salami, boiled eggs, jelly with no added sugar.
Foods allowed in limited quantities:
Cheese: up to 100 g per day
Creams and oils: 2 to 8 tablespoons daily, depending on weight loss goals
Mayonnaise: 2 to 3 tablespoons a day
Lemon juice: up to 4 teaspoons a day
Avocados: 1⁄2 or 1 per day
Dark chocolate at 85%: 2 squares per day
Soy sauce: up to 2 tablespoons per day

Patients were advised that, during the first few days, some people might experience “keto flu” (headache, fatigue, insomnia, body aches, mental fogginess). To reduce the risk of this happening, they were advised to drink plenty of fluids when they are thirsty and to consume broth twice a day (except in cases of hypertension or heart failure).

1. Yancy WS Jr, Olsen MK, Guyton JR, Bakst RP, Westman EC. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial. Ann Intern Med (2004) 140(10):769-77. doi: 10.7326/0003-4819-140-10-200405180-00006

 

 

Food Plan

Breakfast:
Coffee with 2-3 tablespoons of coconut oil or 40-60 g of butter
1 hard-boiled egg or 30 g walnuts or 30 g cheese

Lunch (main meal):
Appetizer (one of the following):
1 egg with 20-30 g mayonnaise Half an avocado
2 sardines
2 mackerel
1 slice of ham
3 small slices of dried salami

Main dish:
100-150 g of meat, seafood or poultry
200-250 g of cooked vegetables from the permitted list (e.g., cauliflower, eggplant or ratatouille) with 2-3 tablespoons of olive oil
Dessert (one of the following):
50 g of cheese
2 squares of 85% dark chocolate 30 g walnuts

Dinner (examples):
Omelet with 2 eggs with ham or cheese
OR
2 fried eggs on ratatouille with 1-2 slices of chorizo
Chicken soup with 2-3 tablespoons olive oil or 30 g cheese or 2 tablespoons sour cream

Snacks:
Participants were given one box of snacks per day containing:
30 g walnuts, 21 g cheese, 2 squares of 85% dark chocolate and one of the following:
1 or 2 hard-boiled eggs
1 egg plus 100 g of sardines or mackerel
3 slices of salami
2 slices of ham, 2 slices of cheese and 1 small cucumber

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