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Treatment in Psychiatry

Treatment in Psychiatry begins with a hypothetical case illustrating a problem in current clinical practice. The authors
review current data on prevalence, diagnosis, pathophysiology, and treatment. The article concludes with the authors'
treatment recommendations for cases like the one presented.

Psychotic and Manic-like Symptoms During Stimulant

Treatment of Attention Deficit Hyperactivity Disorder

Randal G. Ross, M.D. Stimulantsparticularly methylphenidate and am-

phetaminesare a critical first-line option in the treat-
ment of attention deficit hyperactivity disorder (ADHD) in
children and adolescents (1). The potential for stimulants
to induce psychosis-like or manic-like symptoms in chil-
A boy 6 years 9 months of age was dren has been known for at least 35 years, since Lucas and
brought by his mother to a child psychia- Weiss (2) reported on three cases of methylphenidate hal-
trist for difficulties with sustained atten- lucinosis. The terms hallucinosis and toxicosis are of-
tion, distraction, careless errors, poor lis- ten used to distinguish the transient symptoms associated
tening, difficulty following instructions, with stimulant use from the longer-lasting symptoms of
difficulty with organization, frequently schizophrenia and bipolar disorder. The U.S. Food and
misplaced items, and forgetfulness in Drug Administration (FDA), while assessing the signifi-
daily activities. He had no history of im- cance of rare risks in ADHD treatments, recently asked its
pulsive or hyperactive behavior, mood Pediatric Advisory Committee to review reports of stimu-
symptoms, or tics. He had been born af- lant-associated psychotic-like and manic-like symptoms.
ter an unremarkable full-term pregnancy The committee was to comment on the import of the rela-
to a 43-year-old mother who did not use tionship between therapeutic uses of stimulants and psy-
alcohol or drugs during pregnancy. The chosis or mania; whether the benefits of stimulants justify
child was delivered by cesarean section a risk of psychosis or mania; and whether information
after failure to progress in labor and had about risk was adequately relayed to the public (3). This
a normal postnatal course. His family his- case raises the clinical issues of diagnosis and treatment of
tory was negative for mood disorders, psychotic-like and manic-like symptoms arising during
psychosis, obsessive-compulsive symp- stimulant use in children with ADHD.
toms, or tics.
Stimulant-Induced Psychosis or Mania
Several months later, the symptoms had Stimulant medications at high doses can induce symp-
been confirmed in the home, school, and toms of mania and psychosis that are highly similar to
tutoring environments. The patient, then those of bipolar or schizophrenic illnesses (4, 5). These
7 years 4 months of age, was started on symptoms generally resolve within 2 days after discontinu-
methylphenidate, and he showed a clear ation of the stimulant, although symptoms lasting 6 days
dose-response effect. An extended-re- or longer have been reported (5). The pharmacologic ef-
lease formulation of methylphenidate fects of stimulants include the ability to increase dopamin-
was then prescribed, and the dose was ergic and noradrenergic neurotransmission. Observations
gradually increased over a 2-month pe- of clinical similarities between schizophrenia and stimu-
riod to 40 mg per day. At this dose, the lant-induced psychosis provided initial evidence support-
patient had a strongly beneficial re- ing the dopaminergic theory of schizophrenia (6), and
sponse, and the only side effect noted more recent observations suggest that the psychosis seen
was mild anorexia. Eight months later, at in methamphetamine abusers reflects an interaction be-
8 years 3 months of age, after a flu-like tween substance abuse and an underlying vulnerability to
illness, he developed new symptoms, psychosis (7). Thus, symptoms induced by high doses of
which included complaints of hearing stimulants may provide a window into understanding
voices and seeing adults when no one some forms of psychosis and mania.
was present, a desire to throw himself
down the stairs, high levels of anxiety,
Therapeutic Doses of Stimulants
tearfulness at school, an unwillingness to
leave his mothers side, and irritability. Anecdotal reports (8) have been published on the rela-
tion between therapeutic doses of stimulants and mania or
psychosis, but the topic has not been closely examined. Re-
cently, the FDA reviewed several pharmaceutical com-

Am J Psychiatry 163:7, July 2006 1149


pany-sponsored trials of methylphenidate formulations, ulant; all five of these patients were rediagnosed as hav-
amphetamine salts, modafinil, and atomoxetine (912). ing either bipolar disorder or schizophrenia.
Combining across stimulant medications, during double- Predicting who is at risk of stimulant toxicosis is prob-
blind, placebo-controlled trials, placebo was not associ- lematic. The case reports are notable for a broad range in
ated with any toxicosis events in 3,990 subjects with a com- patients ages (217 years), a variety of medications, a wide
bined duration of treatment of over 425 years. For thera- range for duration of exposure, the symptoms reported,
peutic doses of active medication, there were 13 reports of and symptom severity. The cases are similar only in the
toxicosis in 5,717 subjects with a combined treatment du- generally brief duration of stimulant-induced symptoms:
ration of over 800 years. In open-label trials, stimulants recovery typically occurs within 2 daysand almost al-
were associated with 45 reports of toxicosis in 15,999 sub- ways within 7 daysof discontinuing the medication or
jects with a combined treatment dura- lowering the dose. Moreover, with dis-
tion of almost 9,400 years. Although continuation of the stimulant, the re-
there are methodological problems in These numbers emergence of ADHD symptoms is typ-
summing across stimulant medica-
tions and across studies that may have
suggest. . . that toxicosis ically rapid. Family history is unlikely
to be a useful clinical predictor. Even
different sensitivities for identifying will occur in among children with a first-degree rel-
psychotic-like and manic-like symp- ative with schizophrenia or bipolar
toms, these numbers suggest as a pre-
approximately 0.25% disorder, attentional dysfunction
liminary estimate that toxicosis will of children treated with without later onset of psychosis or
occur in approximately 0.25% of chil- mania is more common than atten-
dren treated with stimulants, or about
stimulants, or tional dysfunction preceding psycho-
1 in 400a proportion suggesting an about 1 in 400. sis or mania (21, 22). Moreover, chil-
infrequent but not rare effect of thera- dren with the more common forms of
peutic dosing. pediatric bipolar disorder may benefit
The severity and duration of stimulant-induced toxico- from stimulant medication (23). In short, stimulant-in-
sis were also examined. In the FDA studies, a broad array duced toxicosis appears to be truly idiosyncratican im-
of search terms was used to identify cases of possible toxi- portant but infrequent and unpredictable side effect of
cosis in pharmaceutical company-sponsored trials. Al- stimulant treatment.
though this approach is highly sensitive in identifying
cases of toxicosis, it also identifies cases with less specific A Marker of Vulnerability
and less severe symptoms, such as anxiety, social with-
Most cases of stimulant toxicosis resolve with discontin-
drawal, aggression, and irritability. When all of these cases
uation of the stimulant. However, attentional dysfunction,
were considered as a group of psychiatric adverse
whether measured by cognitive testing (24) or by ADHD-
events, the most common outcomes were listed as not
like clinical symptoms (25), is a common premorbid pre-
reported or not available. Thus, while the FDA reported
sentation for children who later manifest schizophrenia or
that, depending on the stimulant, 33%58% of cases of
bipolar disorder. Retrospective data from patients with
stimulant-induced psychiatric adverse events resolved
schizophrenia or bipolar disorders document high rates of
with discontinuation of the drug, the use of broad search
childhood stimulant usegenerally higher even than
criteria and the lack of outcome data make these numbers
other groups with attentional dysfunction (26) and histo-
difficult to interpret.
ries of stimulant-associated adverse behavioral effects
An alternative approach to examining adverse out-
(27). In these patients, a history of stimulant use is also as-
come data was used in a contribution (13) to the recent
sociated with an earlier age at onset (28) and a more severe
national discussion on the relationship between antide-
course of illness during hospitalization (29). Stimulant ex-
pressants and suicidal thoughts. Individually identified
posure in vulnerable individuals may hasten the onset or
cases in the FDA database were subjected to expert re-
worsen the course of bipolar or schizophrenic illnesses
view, focusing on particularly clear cases. In an attempt
(26, 30). Thus, while stimulants are clearly beneficial for
to follow this approach, I examined case reports from
the vast majority of children with ADHD, there may be a
FDA publications (912) and the literature (2, 1420) in
small subgroup for whom the medications worsen the
which descriptive summaries were presented of psy-
long-term course of other illnesses. Research aimed at de-
chotic-like or manic-like symptoms occurring during
termining whether such a subgroup exists and how to
stimulant treatment, in which stimulant treatment was
identify it is warranted.
discontinued or reduced, and in which outcome was
discussed. Data were available for 60 cases. In 55 cases
(92%), the psychotic-like or mania-like symptoms re-
solved, and hence these cases might be better termed Stimulants are highly beneficial for children with ADHD
stimulant toxicosis than psychosis or mania. In the re- and are a valuable component of the treatment armamen-
maining five cases (8%), psychotic symptoms either tarium. However, therapeutic doses of stimulants can
continued or recurred after discontinuation of the stim- cause manic-like or psychotic-like symptoms in a small

1150 Am J Psychiatry 163:7, July 2006


proportion of treated children. These symptoms can in- week later, and the symptoms did not re-
clude euphoria, grandiosity, paranoid delusions, confu- cur. The patient, now 11 years 4 months
sion, hallucinations, and increased aggression. Other than of age, has been maintained on meth-
a history of sustained psychosis or clear sustained mania, ylphenidate since that time. His atten-
there are no good predictors of such responses. The symp- tional dysfunction remains markedly re-
toms can occur with the first dose or after months of stable duced, and the psychotic-like symptoms
treatment. Thus, caregivers need to be educated about have not recurred.
such side effects. The majority of manic-like and psy-
chotic-like reactions present no immediate danger. How-
ever, when stimulant toxicosis is identified, patients must
be evaluated for symptoms that increase the risk of imme-
diate harm. These include suicidal ideation, command Received April 8, 2006; revision received April 18, 2006; accepted
hallucinations, increased aggressive urges, and impaired April 24, 2006. From the Department of Psychiatry, University of Col-
orado at Denver and Health Sciences Center, Denver. Address corre-
judgment. If symptoms are not severe or the child is spondence and reprint requests to Dr. Ross, Department of Psychia-
young, increased or continuous direct parental supervi- t r y, B o x C 2 6 8 - 3 1 , 4 2 0 0 E . 9 t h A v e . , D e n v e r, C O 8 0 2 6 2 ;
sion is indicated; if symptoms are severe and the child is (e-mail).
Supported by NIH grants MH-056539 and MH-068582.
older, urgent or emergent evaluation by an experienced
Dr. Ross owns shares of Johnson & Johnson stock. Dr. Freedman has
mental health professional is warranted. Discontinuation reviewed this article and found no evidence of influence from this re-
of the stimulant during the acute toxicosis is generally the lationship.
best approach. After discontinuation of the stimulant,
stimulant toxicosis generally resolves within 2448 hours
and almost always within 7 days. Currently, there is no References
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