Site PIs David Miklowitz, Ph.D., Distinguished Professor of Psychiatry, University of
California, Los Angeles
Danella Hafeman, M.D. and Boris Birmaher, MD, University of Pittsburgh School of
Medicine;
Christopher Schneck MD (site PI), Melissa Batt, MD (co-PI), and Aimee Sullivan, PhD,
University of Colorado Anschutz Medical Campus, Aurora, CO.
Melissa Delbello, MD (site PI) and L. Rodrigo Patino Duran, MD (Co-PI), University of
Cincinnati College of Medicine
Phase 1: Intake Period and Pre-Treatment Assessments
During the approximately 4-week intake period (phase I) the investigators will conduct a
psychiatric and medical evaluation of the child to determine whether the youth meets
diagnostic, symptom, and keto trial eligibility and the diet is consistent with the
youth's health goals.
Phase I: Evaluation Phase Steps
An initial phone screen will be completed with potential young adult participants,
or one or more parents or legal guardians for potential minor participants. If they
remain potentially eligible and interested, they will be invited to come to the
clinic for the consenting process. If a minor has two parents or guardians with
legal rights to health care decision making, both parents need to sign consents.
If youth and their parent(s) assent/consent, they will move on to phase 1
psychiatric evaluation (diagnostic interview, symptom assessment, psychiatric and
medical history) with a study psychologist and psychiatrist
Families and youth will go to the UCLA Clinical and Translational Research Center
(CTRC) for venipuncture and a urine sample. Blood draws will be performed by either
certified phlebotomy technicians or registered nurses. Intake blood tests required
prior to starting keto diets include lipids, insulin, glucose, thyroid-stimulating
hormone test, A1C, and cholesterol (see Table 2 for a complete list); total blood
volume to be collected at intake is a little less than 2 tablespoons)
Families and youth will next meet with the study dietitian (Denise Potter, RDN or
her designee) who will (a) perform a separate assessment of the child's eligibility
for the study, and (b) provide education about the diet (e.g., expected benefits and
side effects, the importance of regular ketone assessments). Study clinicians
(psychiatrists, psychologists, and dietitians) will jointly determine the youth's
eligibility in term of diagnosis, symptom status, and health for initiation of keto
therapy, which begins in phase II.
If youth is eligible for ketogenic therapy and decides to continue, they will be
invited to continue and to next meet with a study therapist (e.g., psychologist,
social worker, MH counselor) for (a) a 45-60 min family psychoeducation session
concerning how to cope with BSDs (for example, how to recognize prodromal symptoms
of mania and work with the treatment team to prevent recurrences) and the role of
nutrition; and (b) a 45-min individual session for the youth ("motivational
enhancement" sessions) to explore the youth's health-related goals, values, and
motivation for initiating and completing the diet phase.
Following best practice guidelines for the treatment of bipolar disorder participants
will be assigned a study psychiatrist with expertise in pediatric mood disorders for
their initial medication consultation. During the 16-week keto trial, the psychiatrist
will review lab and test results and meet with youth/parents at least monthly to oversee
safety of medications prescribed. The psychiatrist will work to stabilize the youth on
psychiatric medications prior to initiation of diet therapy in phase II. However, this is
not a psychopharmacology study: youth are not required to start or stop any medications
to participate in the keto phase (II) of the study. During the monthly visits,
psychiatrists will help participants address any side effects or safety concerns,
including making clinically necessary medication adjustments (e.g., increasing the dose
of a mood stabilizer to treat depression). Psychiatrists will coordinate with the study's
registered dietitian and other relevant care professionals (e.g., the youth's GP) as
needed. This plan for psychiatrist care aligns with best practice guidelines for youth
with BSDs.
Phase II: Ketogenic Preparation and "Ramp Up"
Once the youth and parents have consented to the study and been determined to be eligible
for keto therapy, phase II will begin with a 2-3 week period of diet adjustment or
"ramping up." During this 2-3 week period, they will meet with the dietitian weekly to
discuss some simple keto recipes (e.g., for lunch) and problem-solve regarding barriers
to implementing the diet. This period helps reduce the likelihood of side effects from
the transition in diet (e.g., Keto flu) by easing the participant into the low carb state
and getting them used to self-administered blood ketone assessments. This is
accomplished, for example, by cutting out sugar and introducing a single self-prepared
keto meal each day for one week, and then two keto meals in the second week, and three in
the third. Prior to starting the official diet, participants will complete a pre-diet
assessment of mood symptoms, psychosocial functioning, surveys, and brief
neuropsychological testing. They will also take pictures of their meals and snacks for 3
days prior to phase III (to be uploaded to a HIPAA-compliant box folder and shared with
the dietitian and study team). If the youth has adjusted well during the ramp up period,
the diet therapy trial (phase III) will be initiated and the 16-week diet therapy clock
will start.
Phase III. Keto Therapy Trial
During the keto therapy phase (16 weeks), the dietitian will help the family and youth
order keto meals from Factor 75 (a food delivery service), with adjustments made as
necessary from weekly dietitian coaching sessions. The prescribed keto diet aligns with
practice guidelines of the International Ketogenic Diet Study Group for youth. The family
may choose to buy their own groceries and cook their own keto meals for the youth rather
than having the meals delivered, and if so they will be compensated for groceries on a
per diem basis by the study. The dietitian will monitor the youth's dietary intake,
baseline blood ketone and lipid/cholesterol/insulin/glucose values, and potential dietary
side effects at weekly visits. The youth be asked to take a daily self-administered blood
test (fingerprick) using a "Keto Mojo" meter provided to them, which will tabulate level
of ketones and glucose. These readings will be entered into a HIPAA-compliant server and
accessed by the study dietitian and research team. The repeat readings will help
determine whether the youth achieves and maintains a state of ketosis, which is the goal
of ketogenic diets.
The youth will return to the CTRC lab for a repeat blood test (glucose, lipids,
inflammatory markers, etc.; see Table 2 for complete list of tests) at 8 weeks
(mid-treatment) and 16 weeks (end of study) so that the dietitian and psychiatrist can
track the youth's health and response to the diet. Independent evaluators will interview
participants every 4 weeks through the 16-week study for symptoms (e.g., depression,
mania, anxiety, mood instability) and psychosocial functioning.
Phase IV: Post-Treatment Assessments
At the end of the 16-week keto trial, a post-treatment evaluation will be conducted with
the same measures (symptom assessments, neuropsychological functioning, psychosocial
functioning) done at intake. Participants will be compensated for completing all research
measures.
Specific Aims
Hypothesis #1: Diet Adherence and Tolerance. An estimated 60 youth (15 per site) in
bipolar depressed or mixed states (depressed with hypomanic or manic symptoms) will be
cleared for initiation of the 16-week keto diet following an initial 4-6-week intake
assessment and preparation period. The investigators expect 40 (10 per site) to complete
the 16-week keto therapy trial and post-assessment. The investigators will assess the
proportion of youth who maintain ketosis, as measured through (a) daily blood ketone
assays using the Keto Mojo device, a Bluetooth-enabled ketone and glucose testing kit,
and (b) photographs of food intake (meals, drinks, and snacks) one day per week. The
investigators will assess diet tolerance and safety through calculating the proportion of
youth staying on the diet, parent and youth reports of side effects, and dietitian- and
independent evaluator-collected side effect questionnaires. The investigators hypothesize
that with appropriate coaching, the investigators will observe keto diet compliance rates
of 70-80%. The investigators hypothesize that the diet will be sufficiently tolerated,
with family participants and clinicians reporting that side effects are manageable.
Hypothesis #2: Symptom Improvement. Youth with high compliance to the 16-week keto diet
will have significant reductions in bipolar depressive symptoms from baseline to
completion of the 16-week diet, without concomitant increases in hypomanic symptoms. The
investigators further expect that they will show significant reductions in mood
instability and increases in Global Assessment of Functioning scores (rated on a 1-100
scale).
Hypothesis #3. Metabolic Indicators. Youth with high compliance with the keto diet will
show significant pre- to post-treatment improvement in metabolic indicators (e.g.,
insulin resistance and glucose values (HOMA-IR), inflammatory markers (e.g., CRP), and
cognitive (executive) functioning from baseline to end of treatment.
Background and Significance
Bipolar spectrum disorders (BSDs) affect approximately 2.5% of children and adolescents
worldwide. Youth with BSDs are at high risk for recurrent courses of illness and poor
psychosocial functioning even when receiving pharmacotherapy. When treated with standard
mood stabilizers or antipsychotics, only 43% of adolescents with bipolar I disorder
recover in the year after a hospitalized manic episode; 54% have illness recurrences and
as many as 1 in 3 are treatment refractory. Moreover, only 35% are adherent with
prescribed medications during the post-hospital year. The investigators need more
effective and better-tolerated interventions for youth with bipolar I or II disorder, as
well as those on the bipolar spectrum who are at risk for developing a full-blown bipolar
I or II disorder (i.e., other specified bipolar disorder, with major depressive episodes
alternating with recurrent periods of subthreshold mania or hypomania). The goals of
early intervention for BSD are to fully stabilize youth from existing depressive
episodes, prevent recurrences, and enhance individual functioning.
Depression is the primary unmet concern of most patients with BSD, regardless of age.
Adult and youth patients with bipolar I or II spend three times as many weeks in their
lives in depressive episodes compared to manic or hypomanic episodes. Undertreated
depression is the strongest predictor of cognitive, metabolic and functional impairments
associated with the disorder, including suicidal thoughts/behaviors, attention and memory
impairments; and academic, occupational or social disability. Manic, mixed (depressive
and hypomanic/manic), and hypomanic symptoms and episodes are also highly disruptive and
impairing to youth. Most antipsychotic and mood-stabilizing agents are more effective in
treating manic episodes than depressive or mixed presentations but are also associated
with metabolic side effects such as weight gain and obesity. Clearly, the investigators
need more effective treatments for bipolar depression and mixed phase (depressive and
hypomanic/manic) presentations in youth.
What Can Be Done? Youth with BSD are usually treated with lithium, lamotrigine or second-
generation antipsychotic agents (SGAs) such as lurasidone (Latuda) or aripiprazole
(Abilify). All SGAs are associated with metabolic side effects, although some (e.g.,
lurasidone) cause fewer metabolic side effects than others (e.g., olanzapine). In the
first two years of the Child and Adolescent Bipolar Network (CABIN) study (IRB-22-0309),
the investigators implemented systematic pharmacological algorithms for the choice of
primary and secondary agents, adjusting dosages, combining agents, and using adjunctive
treatments to address side effects (for example, Metformin) in youth with bipolar
depression or hypo/mania. In the CABIN study, there was substantial agreement among
expert psychiatrists as to what medications were first and second-line choices for
bipolar depression, mania, and mixed phases, whether bipolar I, II, or other specified in
subtype. Nonetheless, it is clear to us from this and many other studies that a large
proportion of youth with BSDs do not respond adequately to evidence-based medications
alone.
Youth with or at risk for BSD are likely to have a long treatment course ahead of them
and challenges with recovery. Testing whether ketogenic therapy - given adjunctively to
pharmacotherapy - can help stabilize depressive or mixed symptoms and enhance cognitive
and metabolic functioning in youth with BSD is of significant public health importance.
To test the efficacy of keto therapy combined with pharmacotherapy, the investigators
need to start with an open trial to test tolerability, feasibility, and adherence rates,
and to determine whether there are clinical benefits that warrant evaluation in a
randomized controlled trial.
Diet and Nutrition What is the role of diet and nutrition in the effort to stabilize mood
episodes in bipolar youth? There is growing evidence that ketogenic diets are associated
with mood improvement in adult bipolar patients and reductions in seizures in children
with treatment- refractory epilepsy. As in epilepsy, BSDs are associated with
neuroinflammation and oxidative stress. The ketogenic diet operates through strengthening
antioxidant defenses, improving mitochondrial function, and regulating inflammatory
genes.
There is increasing evidence that ketogenic diets are associated with improvements in
executive functioning in elderly patients - enhanced working memory, planning ability,
mental flexibility, and self-control. Executive functioning is impaired in bipolar
disorder and is often in evidence even when individuals are not in a mood episode.
Whether ketogenic diets improve executive functioning in psychiatric patients has not
been adequately tested.
Importantly, ketogenic or other nutrition plans have never been tested systematically in
youth with BSDs. This study provides a unique opportunity to test the mood- stabilizing
effects of adjunctive ketogenic therapy and identify which subgroups of bipolar youth
respond optimally to it. The investigators hypothesize that in a 16-week open trial youth
with bipolar disorder will show substantial mood improvement on the combination of
standard of care pharmacotherapy and ketogenic diets. In secondary analyses, the
investigators will explore whether diet adherence (e.g., days in ketosis, as indicated by
daily blood ketosis values and estimates of grams of carbohydrates consumed) is
correlated with levels of improvement in mood and cognitive functioning over 16 weeks.
Youth with BSDs tend to have more impairment in metabolic indices such as BMI than their
age-mates. Teens with impaired metabolic functioning are also likely to have poorer
executive functioning. Although weight loss is not the purpose of keto therapy, t is
possible that in early-onset BD, the subgroup of youths with impaired metabolic
functioning will show the most symptom benefit and cognitive improvement with ketogenic
diets. Indeed, a 12-week study in overweight teens found that a high fat,
low-carbohydrate diet was associated with greater weight loss than a low-fat diet, and
more improvement in HDL-C and triglyceride levels. In secondary analyses the
investigators will explore the effects of a ketogenic diet on BMI and executive
functioning over 16 weeks.
Research Design and Methods: Study Stages
This study is divided into four stages as follows, with more details on the steps and
responsible staff noted in Table 1:
Phase I (~4 weeks total): the intake phase, where the potential participant is screened
by telephone, consented for the study, and administered a battery of diagnostic and
biological assays to determine study-eligibility.
Phase II (2-3 weeks total): the pre-keto preparatory phase, in which the youth will "ramp
up" to the full 3 meal/day keto program by eating one keto meal per day in the first
week, two in the second, and 3 in the third. The youth will also complete a pretreatment
battery of symptom, functioning, and neuropsychological measures at this phase
(interviews and self-report surveys).
Phase III (16 weeks total): the keto therapy trial.
Phase IV (1 week): the closing assessment and feedback phase.