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. 2022 Jul 13;7(7):CD013136.
doi: 10.1002/14651858.CD013136.pub2.

Stimulant and non-stimulant drug therapy for people with attention deficit hyperactivity disorder and epilepsy

Chris Eaton  1   2 , Kenneith Yong  3 , Victoria Walter  4 , Gashirai K Mbizvo  5 , Sinead Rhodes  1 , Richard Fm Chin  4
Affiliations

Stimulant and non-stimulant drug therapy for people with attention deficit hyperactivity disorder and epilepsy

Chris Eaton et al. Cochrane Database Syst Rev. .

Abstract
in English, Spanish

Background: Attention Deficit Hyperactivity Disorder (ADHD) can co-occur in up to 40% of people with epilepsy. There is debate about the efficacy and tolerability of stimulant and non-stimulant drugs used to treat people with ADHD and co-occurring epilepsy.

Objectives: To assess the effect of stimulant and non-stimulant drugs on children and adults with ADHD and co-occurring epilepsy in terms of seizure frequency and drug withdrawal rates (primary objectives), as well as seizure severity, ADHD symptoms, cognitive state, general behaviour, quality of life, and adverse effects profile (secondary objectives).

Search methods: We searched the following databases on 12 October 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 9 October 2020), CINAHL Plus (EBSCOhost, 1937 onwards). There were no language restrictions. CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups including Epilepsy. SELECTION CRITERIA: We included randomised controlled trials of stimulant and non-stimulant drugs for people of any age, gender or ethnicity with ADHD and co-occurring epilepsy.

Data collection and analysis: We selected articles and extracted data according to predefined criteria. We conducted primary analysis on an intention-to-treat basis. We presented outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), except for individual adverse effects where we quoted 99% CIs. We conducted best- and worst-case sensitivity analyses to deal with missing data. We carried out a risk of bias assessment for each included study using the Cochrane risk of bias tool and assessed the overall certainty of evidence using the GRADE approach.

Main results: We identified two studies that matched our inclusion criteria: a USA study compared different doses of the stimulant drug osmotic-release oral system methylphenidate (OROS-MPH) with a placebo in 33 children (mean age 10.5 ± 3.0 years), and an Iranian study compared the non-stimulant drug omega-3 taken in conjunction with risperidone and usual anti-seizure medication (ASM) with risperidone and ASM only in 61 children (mean age 9.24 ± 0.15 years). All children were diagnosed with epilepsy and ADHD according to International League Against Epilepsy and Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria, respectively. We assessed both studies to be at low risk of detection and reporting biases, but assessments varied from low to high risk of bias for all other domains. OROS-MPH No participant taking OROS-MPH experienced significant worsening of epilepsy, defined as: 1. a doubling of the highest 14-day or highest two-day seizure rate observed during the 12 months before the trial; 2. a generalised tonic-clonic seizure if none had been experienced in the previous two years; or 3. a clinically meaningful intensification in seizure duration or severity (33 participants, 1 study; low-certainty evidence). However, higher doses of OROS-MPH predicted an increased daily risk of a seizure (P < 0.001; 33 participants, 1 study; low-certainty evidence). OROS-MPH had a larger proportion of participants receiving 'much improved' or 'very much improved' scores for ADHD symptoms on the Clinical Global Impressions for ADHD-Improvement tool (33 participants, 1 study; low-certainty evidence). OROS-MPH also had a larger proportion of people withdrawing from treatment (RR 2.80; 95% CI 1.14 to 6.89; 33 participants, 1 study; moderate-certainty evidence). Omega-3 Omega-3 with risperidone and ASM were associated with a reduction in mean seizure frequency by 6.6 seizures per month (95% CI 4.24 to 8.96; 56 participants, 1 study; low-certainty evidence) and an increase in the proportion of people achieving 50% or greater reduction in monthly seizure frequency (RR 2.79, 95% CI 0.84 to 9.24; 56 participants, 1 study; low-certainty evidence) compared to people on risperidone and ASM alone. Omega-3 with risperidone and ASM also had a smaller proportion of people withdrawing from treatment (RR 0.65, 95% CI 0.12 to 3.59; 61 participants, 1 study; low-certainty evidence) but a larger proportion of people experiencing adverse drug events (RR 1.40, 95% CI 0.44 to 4.42; 56 participants, 1 study; low-certainty evidence) compared to people on risperidone and ASM alone.

Authors' conclusions: In children with a dual-diagnosis of epilepsy and ADHD, there is some evidence that use of the stimulant drug OROS-MPH is not associated with significant worsening of epilepsy, but higher doses of it may be associated with increased daily risk of seizures; the evidence is of low-certainty. OROS-MPH is also associated with improvement in ADHD symptoms. However, this treatment was also associated with a large proportion of treatment withdrawal compared to placebo. In relation to the non-stimulant drug omega-3, there is some evidence for reduction in seizure frequency in children who are also on risperidone and ASM, compared to children who are on risperidone and ASM alone. Evidence is inconclusive whether omega-3 increases or decreases the risk of adverse drug events. We identified only two studies - one each for OROS-MPH and omega-3 - with low to high risk of bias. We assessed the overall certainty of evidence for the outcomes of both OROS-MPH and omega-3 as low to moderate. More studies are needed. Future studies should include: 1. adult participants; 2. a wider variety of stimulant and non-stimulant drugs, such as amphetamines and atomoxetine, respectively; and 3. additional important outcomes, such as seizure-related hospitalisations and quality of life. Clusters of studies which assess the same drug - and those that build upon the evidence base presented in this review on OROS-MPH and omega-3 - are needed to allow for meta-analysis of outcomes.

Antecedentes: El trastorno por déficit de atención e hiperactividad (TDAH) puede concurrir en hasta el 40% de las personas con epilepsia. Existe un debate sobre la eficacia y la tolerabilidad de los fármacos estimulantes y no estimulantes utilizados para tratar a las personas con TDAH y epilepsia concurrente.

Objetivos: Evaluar el efecto de los fármacos estimulantes y no estimulantes en niños y adultos con TDAH y epilepsia concurrente, en cuanto a la frecuencia de las crisis epilépticas y las tasas de retiro del fármaco (objetivos principales), así como la gravedad de las crisis epilépticas, los síntomas del TDAH, el estado cognitivo, el comportamiento general, la calidad de vida y el perfil de efectos adversos (objetivos secundarios). MÉTODOS DE BÚSQUEDA: El 12 de octubre de 2020 se realizaron búsquedas en las siguientes bases de datos: Registro Cochrane de Estudios (CRS Web), MEDLINE (Ovid, 1946 hasta el 9 de octubre de 2020), CINAHL Plus (EBSCOhost, 1937 en adelante). No hubo restricciones de idioma. El CRS Web incluye ensayos controlados aleatorizados o cuasialeatorizados de PubMed, Embase, ClinicalTrials.gov, la Plataforma de registros internacionales de ensayos clínicos (ICTRP) de la Organización Mundial de la Salud, el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials; CENTRAL) y los registros especializados de los Grupos Cochrane de Revisión, incluido el de Epilepsia. CRITERIOS DE SELECCIÓN: Se incluyeron ensayos controlados aleatorizados de fármacos estimulantes y no estimulantes para personas de cualquier edad, sexo o etnia con TDAH y epilepsia concurrente. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se seleccionaron los artículos y se extrajeron los datos según criterios predefinidos. El análisis principal se realizó por intención de tratar. Los desenlaces se presentaron como razones de riesgos (RR) con intervalos de confianza (IC) del 95%, excepto en el caso de los efectos adversos individuales, en los que se citaron los IC del 99%. Se realizaron análisis de sensibilidad en el mejor y peor de los casos para lidiar con los datos faltantes. Se realizó una evaluación del riesgo de sesgo para cada estudio incluido mediante la herramienta Cochrane de riesgo de sesgo y la certeza general de la evidencia se evaluó mediante el método GRADE.

Resultados principales: Se identificaron dos estudios que cumplieron con los criterios de inclusión: un estudio de EE.UU. comparó diferentes dosis del fármaco estimulante metilfenidato con un sistema oral de liberación osmótica (OROS‐MPH) con un placebo en 33 niños (media de edad 10,5 ± 3,0 años), y un estudio iraní comparó el fármaco no estimulante omega‐3 tomado junto con la risperidona y la medicación anticonvulsiva (MAC) habitual con la risperidona y la MAH solamente en 61 niños (media de edad 9,24 ± 0,15 años). Todos los niños tenían un diagnóstico de epilepsia y TDAH según los criterios de la International League Against Epilepsy y del Diagnostic and Statistical Manual of Mental Disorders, cuarta edición, respectivamente. Se consideró que ambos estudios tenían un riesgo de sesgo de detección y de notificación bajos, pero las evaluaciones variaron de riesgo de sesgo bajo a alto en todos los demás dominios. OROS‐MPH Ningún participante de los que recibieron OROS‐MPH presentó un empeoramiento significativo de la epilepsia, definido como: 1. una duplicación de la tasa más alta de convulsiones en 14 días o en dos días, observada durante los 12 meses anteriores al ensayo; 2. una convulsión tónico‐clónica generalizada si no se había experimentado ninguna en los dos años anteriores; o 3. una intensificación clínicamente significativa de la duración o la gravedad de las convulsiones (33 participantes, un estudio; evidencia de certeza baja). Sin embargo, las dosis más altas de OROS‐MPH predijeron un mayor riesgo diario de presentar una convulsión (p < 0,001; 33 participantes, un estudio; evidencia de certeza baja). Con el OROS‐MPH hubo una mayor proporción de participantes que recibieron puntuaciones de "mucha mejoría" o "muchísima mejoría" en los síntomas del TDAH según la herramienta Clinical Global Impressions for ADHD‐Improvement (33 participantes, un estudio; evidencia de certeza baja). Con el OROS‐MPH también hubo una mayor proporción de personas que se retiraron del tratamiento (RR 2,80; IC del 95%: 1,14 a 6,89; 33 participantes, un estudio; evidencia de certeza moderada). Omega‐3 El omega‐3 con la risperidona y la MAC se asociaron con una reducción de la frecuencia media de las crisis epilépticas en 6,6 crisis epilépticas por mes (IC del 95%: 4,24 a 8,96; 56 participantes, un estudio; evidencia de certeza baja) y un aumento de la proporción de personas que lograron una reducción del 50% o más en la frecuencia mensual de las crisis epilépticas (RR: 2,79; IC del 95%: 0,84 a 9,24; 56 participantes, un estudio; evidencia de certeza baja) en comparación con las personas que recibieron risperidona y MAC solamente. Con el omega‐3 con risperidona y MAC también hubo una menor proporción de personas que se retiraron del tratamiento (RR 0,65; IC del 95%: 0,12 a 3,59; 61 participantes, un estudio; evidencia de certeza baja), pero una mayor proporción de personas que presentaron eventos adversos al fármaco (RR 1,40; IC del 95%: 0,44 a 4,42; 56 participantes, un estudio; evidencia de certeza baja) en comparación con las personas que recibieron risperidona y MAC solamente.

Conclusiones de los autores: En los niños con un doble diagnóstico de epilepsia y TDAH, hay alguna evidencia de que el uso del fármaco estimulante OROS‐MPH no se asocia con un empeoramiento significativo de la epilepsia, pero las dosis más altas podrían estar asociadas con un mayor riesgo diario de crisis epilépticas; la evidencia es de certeza baja. OROS‐MPH también se asocia con una mejoría de los síntomas del TDAH. Sin embargo, este tratamiento también se asoció con una gran proporción de retiro del tratamiento en comparación con el placebo. En relación con el fármaco no estimulante omega‐3, existe alguna evidencia de una reducción de la frecuencia de las convulsiones en los niños que también recibieron risperidona y MAC, en comparación con los niños que sólo recibieron risperidona y MAC. La evidencia no es concluyentes en cuanto a si los omega‐3 aumentan o disminuyen el riesgo de experimentar efectos adversos de los medicamentos. Sólo se identificaron dos estudios (uno con OROS‐MPH y otro con omega‐3) con un riesgo de sesgo bajo a alto. La certeza general de la evidencia para los desenlaces de OROS‐MPH y omega‐3 se consideró baja a moderada. Se necesitan más estudios. Los estudios futuros deberían incluir: 1. participantes adultos; 2. una mayor variedad de fármacos estimulantes y no estimulantes, como las anfetaminas y la atomoxetina, respectivamente; y 3. desenlaces adicionales importantes, como las hospitalizaciones relacionadas con las convulsiones y la calidad de vida. Se necesitan grupos de estudios que evalúen el mismo fármaco (y estén desarrollados sobre evidencia presentada en esta revisión acerca de OROS‐MPH y omega‐3) para poder realizar un metanálisis de los desenlaces.

Trial registration: ClinicalTrials.gov NCT00323947.

PubMed Disclaimer

Conflict of interest statement

CE: none to declare

KY: none to declare

VW: none to declare

GM: none to declare

SR: none to declare

RC: has provided consultancy for Eisai, GW Pharma, Zogenix. He has received payment for lectures from GW Pharma, Zogenix and has received support for attendance to a conference to present results of a separate Eisai sponsored study. RC has shares in RIZE Medical Cannabis and Life Sciences. RC monies are paid to his institution.

Figures

1
1
Study flow diagram
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: OROS‐MPH versus placebo, Outcome 1: Proportion of people withdrawing from treatment ‐ primary outcome
1.2
1.2. Analysis
Comparison 1: OROS‐MPH versus placebo, Outcome 2: Individual adverse drug events ‐ secondary outcome
2.1
2.1. Analysis
Comparison 2: Omega‐3 (risperidone & previous ASM) versus risperidone and previous ASM only, Outcome 1: Seizure frequency (monthly, postintervention) ‐ primary outcome
2.2
2.2. Analysis
Comparison 2: Omega‐3 (risperidone & previous ASM) versus risperidone and previous ASM only, Outcome 2: Proportion of individuals withdrawing from treatment ‐ primary outcome
2.3
2.3. Analysis
Comparison 2: Omega‐3 (risperidone & previous ASM) versus risperidone and previous ASM only, Outcome 3: Proportion of people achieving 50% or greater reduction in monthly seizure frequency (change from baseline) ‐ secondary outcome
2.4
2.4. Analysis
Comparison 2: Omega‐3 (risperidone & previous ASM) versus risperidone and previous ASM only, Outcome 4: Best‐case scenario: proportion of people achieving 50% or more reduction in seizure frequency
2.5
2.5. Analysis
Comparison 2: Omega‐3 (risperidone & previous ASM) versus risperidone and previous ASM only, Outcome 5: Worst‐case scenario: proportion of people achieving 50% reduction in seizure frequency
2.6
2.6. Analysis
Comparison 2: Omega‐3 (risperidone & previous ASM) versus risperidone and previous ASM only, Outcome 6: Proportion of people experiencing adverse drug events ‐ secondary outcome
2.7
2.7. Analysis
Comparison 2: Omega‐3 (risperidone & previous ASM) versus risperidone and previous ASM only, Outcome 7: Individual adverse effects
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