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Stimulant Use in ADHD, Bipolar Discouraged :
Expert in mood disorders cites evidence showing that amphetamines might worsen both illnesses.

By  Patrice Wendling
August 1, 2009

Dr. Nassir Ghaemi is a bit of a maverick. The well-published author and director of the mood disorders and psychopharmacology programs at Tufts Medical Center in Boston likes to step off the well-worn CME lecture track and challenge his audience with the words of ancient philosophers, artists, and economists.

At the annual meeting of the American Academy of Clinical Psychiatrists, he pushed those in attendance even further, asking them to reconsider the widely held view that stimulant treatment is relatively safe in attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder.

Dr. Ghaemi contends that children and adults who are diagnosed with ADHD in the United States are automatically given amphetamines, and that there is a routine presumption that long-term treatment with these agents is warranted. He said he believes amphetamines should only be used as a last resort and primarily for short-term treatment in ADHD. In bipolar disorder, he takes the stance that amphetamines should be used even more sparingly–if at all.

The cornerstone of Dr. Ghaemi's arguments lies in emerging evidence that amphetamines might actually worsen ADHD and bipolar disorder.

Some of the first glimmers of this came nearly a decade ago from two retrospective pediatric studies showing a correlation between stimulants and mania. In 42 children with bipolar disorder and ADHD, the mean age of onset of ADHD was 5.5 years, mean length of stimulant use 6.9 years, and onset of manic symptoms 7.1 years (J. Am. Acad. Child Adolesc. Psychiatry 2000;39:713-20).

In 34 adolescents hospitalized with mania, patients with stimulant use before the onset of bipolar disorder had an earlier age at onset of the disease than those without prior stimulant exposure (10.7 vs. 13.9 years). Additionally, adolescents treated with at least two stimulants had a younger age at onset than those treated with one stimulant (Bipolar Disord. 2001;3:53-7).

“It's all association, correlational, observational; it's not definitive, it's not causative, but there's room for suspicion that amphetamines might be causing mania in these children,” said Dr. Ghaemi, also a professor of psychiatry at Tufts University who completed a research fellowship in psychopharmacology at Massachusetts General Hospital.

He went on to highlight additional data on treatment-emergent mania. In a brief open study in 14 depressed adults with a DSM-IV diagnosis of bipolar illness treated with methylphenidate added to a mood stabilizer regimen, 3 patients (21%) stopped methylphenidate because of anxiety, agitation, or hypomania (Bipolar Disord. 2000;2:56-9).

A case review of 82 children (mean age 10.6 years) with bipolar disorder not receiving mood stabilizers reported treatment-emergent mania in 20% of 40 children on stimulants–6 of 28 children on methylphenidate and 2 of 12 on amphetamines. The mean time to mania onset was 12.5 days from start of treatment (J. Affect. Disord. 2004:82:149-58).

By themselves, these data are not that alarming, given that antidepressants in the observational setting are associated with roughly a 20% mania switch rate, Dr. Ghaemi said. In the case review, however, long-term harmful effects were observed, including more mood episodes, suicidality, and hospitalization.

In his own study, co-led by former Emory University colleague Dr. Aliza Wingo, the rate of stimulant-associated mania or hypomania reached a staggering 40% in 137 adults with ADHD and bipolar disorder treated mostly with methyl phenidate for varying lengths of time (Psychopharmacol. Bull. 2008;41:37-47). “This is the largest study of adult ADHD bipolar comorbidity, and we're finding that stimulants are harmful in almost one-half of patients,” he said.

Routine and long-term amphetamine use in young children is particularly concerning, Dr. Ghaemi said, because animal studies have shown an association between early amphetamine use and adult neurobiologic effects, including decreased response to rewarding stimuli, increases in depressive and anxiety behaviors, and decreased dopaminergic neuronal activity. In rats given Ritalin at a dose of 2.0 mg/kg twice daily from days 20 to 35 after birth, researchers observed a significant decrease in long-term survival of newborn cells, particularly in the temporal hippocampus (Biol. Psychiatry 2006;60:1121-30).

The way in which this plays out in bipolar disorder is even more remarkable, as the illness itself can reduce cortical thickness, Dr. Ghaemi said. Brain MRIs identified significant decreased cortical thickening in multiple prefrontal cortices in 25 patients with bipolar disorder, relative to 21 healthy controls (Bipolar Disord. 2006;8:65-74). In addition, a correlation was found between illness duration and cortical thinning.

“Amphetamines, if they were newly coming to the market today, I believe they wouldn't make it through [Food and Drug Administration] screening because of this issue,” he said. (The agency has looked recently at the use of stimulants in children and adolescents with ADHD. See article below.)

Dr. Ghaemi's thinking is not so radical, according to Dr. Boghos Yerevanian, clinical professor of psychiatry, University of California, Los Angeles, and director of the mood disorders program at Greater Los Angeles VA Healthcare/Sepulveda.

“I agree with Dr. Ghaemi's observations; they are wise words,” Dr. Yerevanian said in an interview. “There are some data, not as well studied as [they] should be, that long-term stimulant treatment is associated with brain microvascular disease. This further complicates the problem with bipolars whose brain integrity is already compromised due to various factors, some of it known and most unknown. Stroke, of course, is associated with cocaine use in young people and cocaine in many respects mimics amphetamines.”

The next step is for the biologic data to be taken into monkey and human studies, and for the current evidence to be more widely disseminated, Dr. Ghaemi said. “I'm not saying you should stop using amphetamines, but you should think about these data when you're using amphetamines.”

Dr. Ghaemi reported that in the past year he has received research support from Pfizer Inc. and honoraria from Bristol-Myers Squibb. He was on the speakers bureau for Pfizer and Astra-Zeneca but is not currently.

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