1. Treatment Resistant Pediatric BD Elham Shirazi M.D. Board of General Psychiatry Board of Child & Adolescent Psychiatry

2. Pediatric BD: Less adequate treatment response More prolonged & treatment-refractory course More relapse rates More recurrent & intractable More episodes over the course of a year Reduced interepisode recovery

3. Factors associated with nonresponse: 1. Misdiagnosis 2. Poor adherence to treatment 3. Comorbid psychiatric and medical conditions 4. Ongoing exposure to negative events (family conflict, abuse) 5. Quality of treatment

4. Consider whether symptoms persist as a result of: Inadequate response to treatment Or as an expected response to inadequate treatment

5. Step 1 Discontinue potentially destabilizing agents: Antidepressants Can promote mania, mixed states, or rapid cycling in children/ adolescents with BD Can increase the frequency & severity of mood symptoms (Russel E. Scheffer, 2011)

6. Stimulants Can be problematic in patients at risk for BD disorder. Try to discontinue stimulants while stabilizing patients’ mood symptoms Once the patient’s mood symptoms are controlled on a mood stabilizer regimen Using stimulants for comorbid ADHD did not affect relapse rate (Russel E. Scheffer, 2011)

7. Step 2 Optimize the antimanic agents the patient is currently receiving: Serum Li levels between 0.8–1.2 mEq/dl VPA levels between 80–120 mEq/dl Risperidone up to 4 mg/day Olanzapine up to 20 mg/day Quetiapine up to 800 mg/day Now lack of adequate response after a 4-week trial is a “true” treatment failure. (Russel E. Scheffer, 2011)

8. If there is no improvement on a treatment after several months, don’t continue that treatment Use combinations other than the one that hasn’t worked

9. For partial or nonresponders to monotherapy: Combination of 2 mood stabilizers Or of a mood stabilizer with an atypical antipsychotic is indicated Medication combinations are additive both in: Effectiveness & in side effects

10. If remission is achieved on a particular regimen, it should be continued as long as possible At least until the child/adolescent has navigated his most important develpmental, academic, & social milestones.

11. Majority of subjects relapse after the switch to monotherapy A child stabilized on 2 medications needs to be maintained as such since the relapse rate on one drug is high. Even in most treatment responsive youth with PBD, it is common to need 2 mood stabilizers Lithium alone has not been successful in this age group as a maintenance medication.

12. BD + ADHD? In cases where clinicians can not decide between mania & ADHD: If the child becomes more irritable or aggressive with ADHD treatment Use an atypical antipsychotic or a mood stabilizer Followed by retrying the ADHD treatment

13. Keep in mind that “rebound” the apparent return of worse ADHD symptoms at the end of the day Has no diagnostic implications & sometimes subsides over time (Carlson 2003)

14. First-line medication for BP depression: Lamotrigine Lithium Valproate Atypical antipsychotics

15. For partial or non-responders combine with: Another atypical antipsychotics SSRIs Bupropion

16. DMDD + ADHD + ODD Comorbid DBD predict a poorer response to treatment. (Masi 2004, State 2004) A treatment algorithm for ADHD & aggression might be a reasonable course of action (Carlson 2007) Antimanic medications have efficacy as antiaggression medication.

17. Clozapine: Is reserved for the most treatment-resistant cases Because of its side-effect profile. TMS or augmentation with omega-3 fatty acids are yet to be evaluated for treatment of BP depression in youth.

18. ECT: May be indicated for adolescents with severe & most treatment resistant disorders Considered for adolescents with well-characterized BDI who have: Severe episodes of mania or depression Are nonresponsive Or unable to take standard medication therapies.

22. For subjects who do not respond to the initial monotherapy: Treat with one of the other mood stabilizers Or an atypical antipsychotic not previously tried For subjects with a partial response to monotherapy: Combination of 2 mood stabilizers Or of a mood stabilizer with an atypical antipsychotic is indicated

23. Even in most treatment responsive youth with PBD, it is common to need 2 mood stabilizers & a stimulant to treat ADHD symptoms. The clinical course of PBD includes many affective & behavioral bumps. If you attempt to treat all of these bumps it results in excessive polypharmacy. (Russel E. Scheffer, 2011)

24. Also discontinue GABA-ergic agents Gabapentin, Tiagabine, Levetiracetam, Pregabalin GABA-ergic agents frequently cause disinhibition in children Are not effective in treating manic symptoms (Russel E. Scheffer, 2011)

25. Step 3 Use a limited number of mood stabilizers (one or two) Nonconventional & empirically unsupported medications (e.g., oxcarbazepine) are discontinued & replaced with a first-line treatment agent (e.g., Li, VPA, risperidone, olanzapine, or quetiapine) (Russel E. Scheffer, 2011)