The Risk of Treatment-Emergent Mania With Methylphenidate in Bipolar Disorder.
The authors sought to determine the risk of treatment-emergent mania associated with methylphenidate, used in monotherapy or with a concomitant mood-stabilizing medication, in patients with bipolar disorder.



Using linked Swedish national registries, the authors identified 2,307 adults with bipolar disorder who initiated therapy with methylphenidate between 2006 and 2014. The cohort was divided into two groups: those with and those without concomitant mood-stabilizing treatment. To adjust for individual-specific confounders, including disorder severity, genetic makeup, and early environmental factors, Cox regression analyses were used, conditioning on individual to compare the rate of mania (defined as hospitalization for mania or a new dispensation of stabilizing medication) 0-3 months and 3-6 months after medication start following nontreated periods.



Patients on methylphenidate monotherapy displayed an increased rate of manic episodes within 3 months of medication initiation (hazard ratio=6.7, 95% CI=2.0-22.4), with similar results for the subsequent 3 months. By contrast, for patients taking mood stabilizers, the risk of mania was lower after starting methylphenidate (hazard ratio=0.6, 95% CI=0.4-0.9). Comparable results were observed when only hospitalizations for mania were counted.



No evidence was found for a positive association between methylphenidate and treatment-emergent mania among patients with bipolar disorder who were concomitantly receiving a mood-stabilizing medication. This is clinically important given that up to 20% of people with bipolar disorder suffer from comorbid ADHD. Given the markedly increased hazard ratio of mania following methylphenidate initiation in bipolar patients not taking mood stabilizers, careful assessment to rule out bipolar disorder is indicated before initiating monotherapy with psychostimulants.
From the Department of Medical Epidemiology and Biostatistics and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Psychological and Brain Sciences, Indiana University, Bloomington; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm; the Department of Medical Sciences, Örebro University, Örebro, Sweden; and the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Alexander
A
Viktorin
From the Department of Medical Epidemiology and Biostatistics and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Psychological and Brain Sciences, Indiana University, Bloomington; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm; the Department of Medical Sciences, Örebro University, Örebro, Sweden; and the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Eleonore
E
Rydén
From the Department of Medical Epidemiology and Biostatistics and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Psychological and Brain Sciences, Indiana University, Bloomington; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm; the Department of Medical Sciences, Örebro University, Örebro, Sweden; and the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Michael E
ME
Thase
From the Department of Medical Epidemiology and Biostatistics and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Psychological and Brain Sciences, Indiana University, Bloomington; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm; the Department of Medical Sciences, Örebro University, Örebro, Sweden; and the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Zheng
Z
Chang
From the Department of Medical Epidemiology and Biostatistics and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Psychological and Brain Sciences, Indiana University, Bloomington; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm; the Department of Medical Sciences, Örebro University, Örebro, Sweden; and the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Cecilia
C
Lundholm
From the Department of Medical Epidemiology and Biostatistics and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Psychological and Brain Sciences, Indiana University, Bloomington; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm; the Department of Medical Sciences, Örebro University, Örebro, Sweden; and the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Brian M
BM
D'Onofrio
From the Department of Medical Epidemiology and Biostatistics and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Psychological and Brain Sciences, Indiana University, Bloomington; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm; the Department of Medical Sciences, Örebro University, Örebro, Sweden; and the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Catarina
C
Almqvist
From the Department of Medical Epidemiology and Biostatistics and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Psychological and Brain Sciences, Indiana University, Bloomington; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm; the Department of Medical Sciences, Örebro University, Örebro, Sweden; and the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Patrik K E
PK
Magnusson
From the Department of Medical Epidemiology and Biostatistics and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Psychological and Brain Sciences, Indiana University, Bloomington; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm; the Department of Medical Sciences, Örebro University, Örebro, Sweden; and the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Paul
P
Lichtenstein
From the Department of Medical Epidemiology and Biostatistics and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Psychological and Brain Sciences, Indiana University, Bloomington; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm; the Department of Medical Sciences, Örebro University, Örebro, Sweden; and the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Henrik
H
Larsson
From the Department of Medical Epidemiology and Biostatistics and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Psychological and Brain Sciences, Indiana University, Bloomington; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm; the Department of Medical Sciences, Örebro University, Örebro, Sweden; and the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Mikael
M
Landén
D000293:Adolescent; D000328:Adult; D018692:Antimanic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000139:chemically induced* / Q000188:drug therapy*; D000697:Central Nervous System Stimulants / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D012042:Registries; D013548:Sweden; D055815:Young Adult
D018692:Antimanic Agents; D000697:Central Nervous System Stimulants; D008774:Methylphenidate
ADHD; Attention Deficit Hyperactivity Disorder; Bipolar disorder; Methylphenidate; Mood Disorders; Stimulants
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