Child Bipolar Network Ketogenic Diet Approach to Bipolar Disorder in Adolescents

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

1. 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. 2. 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 3. 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) 4. 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. 5. 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 metabo

• Youth Functional Improvement [Срок оценки: From initiation of ketogenic therapy to the end of treatment (up to 16 weeks)]
• Serum Inflammatory Biomarkers (CRP) [Срок оценки: From initiation of ketogenic therapy to the end of treatment (up to 16 weeks)]