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In a previous post, When the FDA Approves a Drug, That Means It's Safe, Right? I discussed why clinical testing prior to FDA approval does not, and cannot, elucidate the full side-effect profile of a drug. Many side effects, including some that are quite serious, are only observed after a drug has won approval.

As with most drug classes, the above point holds true for Attention Deficit Hyperactivity Disorder (ADHD) medications. This is a growing public heath concern, particularly because more and more sub-populations of patients are being prescribed these drugs, and a significant amount of children take them.

There are now links to numerous side effects associated with ADHD drugs that were not apparent during clinical testing. For example, significant associations between ADHD medications and suicidal ideation, aggressive behavior, and psychotic events were only discovered after the drugs were FDA approved. Some of these psychotic side effects have been reported to include visual and tactile hallucinations of snakes, worms, cockroaches, milli-, centi-, and no doubt, zilli-pedes. As far back as 2005, FDA called a meeting to explore these psychotic side effects, and concerns about them continue to grow.

To examine this issue, we searched for links between psychotic events and ADHD medications in the FDA’s repository of post-marketing side effects, the “FDA Adverse Event Reporting System” (FAERS).

 

Methods and Results

The AdverseEvents PV Enterprise application, powered by RxFilter platform was used to systematically search the FAERS database to find links between medications typically used to treat ADHD and psychotic side effects. Drugs examined were: Adderall and Aderall XRE; Ritalin, Ritalin LA, and Ritalin-SR; Focalin & Focalin XR; Concerta; Strattera; Daytrana; and Provigil.

The three tables below list the number of “primary suspect” and “all suspect” case reports for each drug and adverse event group. “HLT” and “PT” refer to “High Level Term” and “Preferred Term” adverse event categories, respectively (as defined by MedDRA). A disproportionality measure known as the “Reporting Odds Ratio” (ROR), along with a corresponding “confidence interval” (CI) range, was calculated for the “primary suspect” cases and is listed in the right hand column. (More on what ROR is, and how it is used, appears after the tables).

 

HLT “Psychotic disorder NEC”

Drug Name

Primary Cases

All Cases

ROR Primary (95% CI)

Adderall, Adderall XR

130

243

17.93 (15.02 – 21.42)

Focalin, Focalin XR

16

24

11.07 (6.72 – 18.23)

Concerta

135

201

9.07 (7.64 – 10.78)

Provigil

56

125

7.16 (5.49 – 9.33)

Ritalin, Ritalin LA, Ritalin-SR

95

218

6.17 (5.03 – 7.56)

Strattera

130

166

2.53 (2.12 – 3.00)

Daytrana

8

10

0.49 (0.24 – 0.98)

 

HLT “Perception disturbances”

Drug Name

Primary Cases

All Cases

ROR Primary (95% CI)

Focalin, Focalin XR

57

71

16.09 (12.19 – 21.22)

Concerta

319

433

8.33 (7.43 – 9.34)

Ritalin, Ritalin LA, Ritalin-SR

238

488

6.03 (5.29 – 6.87)

Adderall, Adderall XR

112

349

5.77 (4.77 – 6.98)

Provigil

102

277

5.00 (4.10 – 6.10)

Strattera

279

352

1.99 (1.78 – 2.25)

Daytrana

33

36

0.70 (0.50 – 0.99)

 

PTs “Hallucinations”

Drug Name

Primary Cases

All Cases

ROR Primary (95% CI)

Focalin, Focalin XR

50

64

15.30 (11.41 – 20.53)

Concerta

296

404

8.46 (7.52 – 9.53)

Ritalin, Ritalin LA, Ritalin-SR

229

463

6.35 (5.56 – 7.26)

Adderall, Adderall XR

109

333

6.16 (5.08 – 7.46)

Provigil

95

253 

5.10 (4.16 – 6.27)

Strattera

244 

313

1.93 (1.70 – 2.19)

Daytrana

28

30

0.67 (0.46 – 0.97)

 

While the case counts above certainly supply interesting information, we don’t know how many units of each of those drugs were sold, so we therefore cannot determine the relative frequency of the adverse events. For example, Daytrana had 33 reported primary cases of the High Level Term “perception disturbances,” while Concerta had 319 cases. It may therefore appear that Concerta is more likely to cause “perception disturbances,” however; one cannot safely make that assumption.

Why? Well, what if Concerta was prescribed 10 times more than Daytrana? If that were the case, then the frequency (per units sold) of the “perception disturbance” side effect would actually be approximately the same for the two drugs.

Accordingly, the right hand columns of the tables display a “disproportionality measure” which is a mathematical method that can be used to determine the “expectedness” of an adverse event in the absence of prescription counts (units sold). ROR is a disproportionality measure of the “reporting strength” association for a given drug and a given adverse event pair. ROR is used to estimate the relative frequency of a specific side effect by comparing its’ prevalence for a given drug with a) other side effects for that same drug, and b) its incidence across other drugs. This measure can be compared with the average, “expected,” rate of the specific adverse event across all drugs, which equals 1.0.

There is no widely accepted benchmark regarding the numerical level at which disproportionality analysis yields a “safety signal,” but many in the drug industry assume relative frequencies above 2.0 warrant deeper scrutiny.

 

Discussion

Many of the disproportionality results listed in the tables are well above what many would consider to be a “safety signal.” Therefore, we believe the post-marketing data presented here add to the accumulating evidence that select members of the ADHD class of medications have disconcertingly high associations with serious psychotic side effects.

In our view, an unacceptable risk/reward ratio is forming for some of these drugs, and this is likely fueled by: 1) growing sub-populations of patients that are being included in prescribing guidelines (1) (2) (3), and 2) a common assumption that these drugs are safe, leading to widespread abuse by students, athletes, and those who assume their use provides a “cognitive edge” (1) (2) (3) (4) (5). In fact, those that abuse these drugs commonly equate them with caffeine. I've had plenty of high-doses of caffeine, and have never “felt” cockroaches crawling under my skin or suddenly considered ending my life.

Addiction, stroke, seizure, withdrawal symptoms, irregular heartbeat, etc. all have been associated with the use of ADHD medications. Adding serious psychotic side effects to that troubling list should highlight the fact that medical gatekeepers need to seriously consider the risk/reward of these drugs, especially with regard to their patients that are not in dire need of these medications.

According to the Substance Abuse and Mental Health Services Administration, over 22,000 emergency room visits were triggered, in 2011 alone, by the use of prescription ADHD drugs.

The continual expansion of both legitimate and non-legitimate usage of these drugs should give all of us pause.

 

Freedom of Information Act Request - FAERS Report download



Keith Hoffman

Keith Hoffman, PhD

Vice President, Scientific Affairs

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Topics: Drug Safety, FDA, Drug / Indication Information

Dr. Keith Hoffman

Written by Dr. Keith Hoffman