FDA Approval Status and Research Evidence Quality - Psychotropic Medications in Children

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Table: FDA Approval Status and Research Evidence Quality - Psychotropic Medications in Children

II. MOOD STABILIZING ANTICONVULSANT AGENTS AND LITHIUM

SECTION CONTRIBUTORS: Robert Kowatch, M.D., Boris Lorberg, M.D., Yana Turkowski, M.D., Julie Zito, Ph.D.

A. LITHIUM

Grade for How Labeled Psychiatric Well Indicated Generic Name Indication for Mood Medication is Comments/ Age (Yrs) Pregnancy (Trade Name) and Stabilization Studied for Pediatric Psychiatric Research for Mood Category Class (Month/Year if Pediatric References/ Other Indications Stabilization available) Mood Stabilization Lithium Carbonate 12+ a Bipolar D isorder - Manic A FDA indication for age 12+ D (Eskalith, Eskalith- episode appears to be extrapolated from CR, Lithobid), research among patients older Lithium Citrate Bipolar Disorder - than 18. Mood stabilizer/ Maintenance therapy Anti-mania/ (Findling et al, 2005, 2011, 2013) Antidepressant (Geller et al., 1998, 2012) (Kowatch, Strawn, et al., 2009) (Dickstein et al., 2009) (Kafantaris et al., 2003, 2004)

In TEAM study, 2nd effective of 3 agents for pediatric Bipolar I mania or mixed mood: risperidone>lithium>valproic acid (Geller et al., 2012), (Vitiello et al., 2012).

B. MOOD STABILIZING ANTICONVULSANT AGENTS

Generic Name Indicated Labeled Psychiatric Grade for How Comments/ Pregnancy (Trade Name) and Age (Yrs) for Indication for Mood Well Pediatric Psychiatric Research Category Class Mood Stabilization (Month/Year Medication is References/ Other Indications Stabilization if available) Studied for Pediatric Mood Stabilization

Carbamazepine 18+ Bipolar I Disorder - Acute C Off-label for pediatric Bipolar D (Carbatrol, Epitol, manic and mixed Disorder. Tegretol,Tegretol episodes (Ginsberg, 2006) XR, Equetro) (Kowatch et al., 2000) Anticonvulsant/ Anti-mania/ FDA-approved 0+ for Epilepsy. Na Channel Antagonist Black Box Warning for aplastic anemia and agranulocytosis, severe dermatologic reactions.

This table does NOT provide recommendations on which medications to use, nor on their relative efficacy or safety. It is NOT a comprehensive list of the medicines that are currently used in the field of child/adolescent psychiatry.

Divalproex sodium 18+ Bipolar I Disorder – Manic A Off-label for pediatric Bipolar D (Depakote, episode Disorder. Depakote (West et al., 2011) Sprinkles, (Pavuluri et al., 2010) Depakote ER, (Kowatch et al., 2009) Depakote DR), (Wagner, Redden, et al., 2009) – Valproate sodium RCT, N=150: negative (Depacon), (Barzman et al., 2006) Valproate/Valproic (DelBello et al., 2006, 2002) Acid (Depakene, (Findling et al, 2005) Stavzor) (Wagner et al., 2002) Anticonvulsant/ Anti-mania/ FDA-approved 10+ for seizures. Antimigraine/ Modulates Black Box Warning for Voltage-Sensitive hepatotoxicity, pancreatitis, Na Channel teratogenic effect.

In TEAM study, least effective of 3 agents for pediatric Bipolar I mania or mixed mood: - risperidone> lithium>valproic acid. (Geller et al., 2012), (Vitiello et al., 2012) Ethosuximide None None D Off-label for pediatric and adult Not (Zarontin) Bipolar Disorder. assigned by Anticonvulsant the FDA FDA-approved 3+ years for Absence seizure. Ethotoin None None D No pediatric or adult psychiatric D (Peganone) research available at this time. Anticonvulsant FDA-approved 1+ years for Complex partial epileptic seizure, Grand mal seizure. Gabapentin None None D Off-label for pediatric and adult C (Neurontin, Bipolar Disorder. Gabarone) (Soutullo et al.,1998, case study) Anticonvulsant/ Anti-neuralgic/ FDA-approved 3+ years for Ca Channel Partial seizure. Effects Lamotrigine 18+ Bipolar I Disorder B Off-label for pediatric Bipolar C (Lamictal, Lamictal Disorder. CD, Lamictal ODT, (Biederman et al., 2010) Lamictal XR) (Pavuluri et al., 2009) Anticonvulsant/ (Chang et al., 2006) Blocks Na Channels/ Inhibits Pediatric add-on trial for manic, Release of mixed, or depressed states was Glutamate completed, results pending.

FDA-approved 2+ for seizures. Black Box Warning for life- threatening skin rash. Levetiracetam None None D No pediatric or adult Bipolar C (Keppra, Keppra indication. XR) Anticonvulsant Should be further studied for potential use in the treatment of Bipolar Disorders (Kaufman, 2004).

FDA-approved 1+ month for

seizures.

Mephobarbital None None D No pediatric or adult Bipolar D (Mebaral) indication or psychiatric research. Anticonvulsant FDA-approved for any age for seizures. Methsuximide None None D No pediatric or adult Bipolar Not (Celontin indication or psychiatric research. assigned by Kapseals) the FDA Anticonvulsant FDA-approved for any age for Absence seizure. Oxcarbazepine None None B Off-label for pediatric, adult C (Trileptal) Bipolar Disorder. Anticonvulsant/ (Wagner, Kowatch, et al., 2006) Antimania/ - RCT N=116 trial: negative Na Channel Antagonist FDA-approved 2+ for Partial seizure. Phenobarbital None None D No pediatric, adult Bipolar D (Luminal) indication. Anticonvulsant/ Hypnotic/ FDA-approved for any age for Increases GABA Epilepsy, Sedation. Transmission Phenytoin None None D No pediatric, adult Bipolar D (Dilantin, Dilantin indication. Infatabs, Dilantin- 125) Off-label for adult Bipolar Anticonvulsant Disorder.

Should be further studied for potential use in the treatment of Bipolar Disorder. (Mishory, 2000)

FDA-approved for any age for seizures Primidone None None D No pediatric, adult Bipolar D (Mysoline) indication. Anticonvulsant Should be further studied for potential use in the treatment of Bipolar Disorder (Schaffer, 1999).

FDA-approved for any age for Epilepsy Tiagabine None None D No pediatric, adult Bipolar C (Gabitril) indication. Anticonvulsant/ GABA Reuptake Should be further studied for Inhibitor potential use in the treatment of Bipolar Disorder. (Carta, 2002)

FDA-approved 12+ for Partial seizure.

Topiramate None None C Off-label for pediatric Bipolar D (Topamax) Disorder. Anticonvulsant/ Blocks Na Off-label for weight gain Channels/ associated with medication side Increases GABA effects. Activity/Inhibits (Delbello, Findling, et al., 2005) Glutamate Release FDA-approved 2+ for seizures. Zonisamide None None D No pediatric, adult Bipolar C (Zonegran) indication. Anticonvulsant/ Na and Ca Should be further studied for Channel Modulator potential use in the treatment of Bipolar Disorder. (Kanba, 1994)

FDA-approved 16+ for Partial seizure.

REFERENCES-SECTION II: MOOD STABILIZING ANTICONVULSANT AGENTS AND LITHIUM

Barzman D.H., DelBello, M.P., Adler, C.M., Stanford, K.E., & Strakowski, S.M. (2006). The efficacy and tolerability of quetiapine versus divalproex for the treatment of impulsivity and reactive aggression in adolescents with co-occurring bipolar disorder and disruptive behavior disorder(s). Journal of Child and Adolescent Psychopharmacology, 16(6):665-70.

Biederman, J., Joshi, G., Mick, E., Doyle, R., Georgiopoulos, A., Hammerness, P., Kotarski, M., Williams, C., & Wozniak, J. (2010). A prospective open-label trial of lamotrigine monotherapy in children and adolescents with bipolar disorder. CNS Neuroscience and Therapeutics, 16(2): 91-102.

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Chang, K., Saxena, K., & Howe, M. (2006). An open-label study of lamotrigine adjunct or monotherapy for the treatment of adolescents with bipolar depression. Journal of the American Academy of Child and Adolescent Psychiatry, 45(3):298- 304.

DelBello, M.P., Kowatch, R.A., Adler, C.M., Stanford, K.E., Welge, J.A., Barzman, D.H., Nelson, E., & Strakowski, S.M. (2006). A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent mania. Journal of the American Academy of Child and Adolescent Psychiatry,45(3):305-13.

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Geller, B., Cooper, T. B. Sun, K., Zimerman, B., Frazier, J., Williams, M., & Heath, J. (1998). Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. Journal of the American Academy of Child and Adolescent Psychiatry, 37(2): 171-178.

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Ginsberg, L.D. (2006). Carbamazepine extended-release capsules: A retrospective review of its use in children and adolescents. Annals of Clinical Psychiatry, 18(Suppl 1):3-7.

Kafantaris, V., Coletti, D. J., Dicker, R., Padula, G., & Kane, J. M. (2003). Lithium treatment of acute mania in adolescents: A large open trial. Journal of the American Academy of Child and Adolescent Psychiatry, 42(9): 1038-1045.

Kafantaris, V., Coletti, D. J., Dicker, R., Padula, G., Pleak, R.R., & Alvir, J. M. (2004). Lithium treatment of acute mania in adolescents: A placebo-controlled discontinuation study. Journal of the American Academy of Child and Adolescent Psychiatry, 43(8): 984-993.

Kanba, S., Yagi, G., Kamijima, K., Suzuki, T., Tajima, O., Otaki, J., Arata, E., Koshikawa, H., Nibuya, M., Kinoshita, N., et al. (1994). The first open study of zonisamide, a novel anticonvulsant, shows efficacy in mania. Progress in Neuro- Psychopharmacology and Biological Psychiatry, 18(4):707-715.

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