ADHD Reading Links: Crashes, Smoking and Drugs

I will be finishing up the April Brain Posts focus on ADHD next week. 

Looking over nearly 300 research abstracts in ADHD published over the last year, five caught my attention.

Here are the five that I will review over the weekend.

I post a more detailed analysis on two of the manuscripts next week.

All reading links include a link to the free full-text manuscript for readers with more interest in a specific topic. Click on the title to be directed to the manuscript.

Risk of Road Crashes in Adult ADHD Drivers

This study examined 777 adult drivers in France who were involved in a road crash. The authors found a diagnosis of ADHD doubled risk for a crash (Odds ratio 2.18) and when ADHD combined with an external distraction the risk was elevated nearly 5-fold (Odds ratio 5.79)

Risk of nicotine use in ADHD

Adolescents with ADHD have higher rates of alcohol, illicit drug use and nicotine use and dependence. However, this association is complex and may relate to higher rates of other disorder in ADHD that drive substance use risk. In this study, adolescents with pure or ADHD only phenotypes did not have increase use of tobacco. Adolescents with ADHD and another disorder (oppositional defiant disorder or conduct disorder) comprised 75% of the sample. This ADHD plus comorbidity group had a 50 % increase in tobacco use compared to controls.

Bupropion in the treatment of adults with ADHD

Stimulants such as methylphenidate and dextroamphetamine form the key drug category in the treatment of ADHD. Non-addictive, non-scheduled drugs are needed to expand clinician treatment options, particularly in populations at risk for drug misuse. Bupropion (a non-addictive antidepressant) has shown some promise in this area. In this manuscript from an Iranian research group, 150 mg of bupropion was superior to placebo in a group of adults with ADHD.

Guanfacine extended release in ADHD (1)
Guanfacine extended release in ADHD (2)

These two studies examine the efficacy and safety of the drug guanfacine in the treatment of ADHD in children. Combined they report findings on over 500 children between the ages of six and seventeen. Both studies found evidence for efficacy of guanfacine over placebo with mild to moderate side effects.

Photo of wood stork is from the author's files.

Follow the author on Twitter WRY999

Melatonin For Tinnitus Clinical Trial

Tinnitus, or persistent ear ringing, has no definitive treatment.  I had recently posted a summary of the status of this disorder based on a research review.

Since that post, a small but important placebo-controlled clinical trial examined the effect of melatonin on a group of subjects with tinnitus.

Here are the key elements of the study design from this clinical trial:
Subjects: Chronic tinnitus of at least 6 months duration as primary complaint (subjects ranged in age from 34 to 86)
Clinical Trial Design: 3 mg melatonin versus placebo for 30 days switchover to other assignment for an additional 30 days
Outcome Measure: Improvement defined as improvement in at least two tinnitus rating scales from 3 administered (Tinnitus Matching, Tinnitus Severity Index, Self-Rated Tinnitus)

In the analysis of the outcome of the trial, 57% of subjects were rated as improved during the melatonin phase while 25% were rated as improved during the placebo phase.   This was a statistically significant difference for the active drug.

Subjects who reported improvement with the melatonin trial were more likely to have the following clinical features:

• male gender
• bilateral tinnitus
• history of loud noise exposure
• no history of previous treatment for tinnitus
• no comorbid anxiety or depression
• higher Tinnitus Matching and Tinnitus Severity Index scores prior to the study

One of the problems with the design in this study is controlling for the potential confounding effect of improved sleep on tinnitus severity reporting.  Individuals who have improvement in sleep with melatonin may generally feel better and report improvement in a variety of domains.  An active non-melatonin comparator hypnotic, i.e. Ambien (zolpidem) would need to be included to determine if melatonin specifically contributes to reducing tinnitus.

The authors note potential mechanisms for melatonin in tinnitus include it's antioxidant effect, autonomic nervous system effects, effects on blood pressure or muscle tone. 

Larger multicenter studies confirming this study result are needed before a significant change in clinical practice can be recommended.  Since melatonin is a generic drug, such a study will likely need public research funding to be completed.

Molecular model of the compound melatonin from the Wikipedia Creative Commons authored by sbrools under the GNU Free Documentation License.

Hurtuk A, Dome C, Holloman CH, Wolfe K, Welling DB, Dodson EE, & Jacob A (2011). Melatonin: can it stop the ringing? The Annals of otology, rhinology, and laryngology, 120 (7), 433-40 PMID: 21859051

Phentermine/Topiramate Combo for Obesity

Molecular Model of Topiramate

Previous Brain Posts summarized some of the pharmacologic agents in the pipeline for weight loss as well as some drug combinations.  A recent research study published in Lancet provides additional data on one of the drug combinations being studied: phentermine and topiramate.

This new study is important because it looked at 56 weeks of treatment and target obese individuals with at least two obesity-related medical complications.  Subjects were required to have significant obesity (BMI 27-45 kg/m2) and at least two of the following:  hypertension, dyslipidemia, diabetes or prediabetes, abdominal obesity).  Each of these factors increases the risk of mortality associated with being overweight.

The key findings from the study--number of pounds lost at 56 weeks:

• placebo-- 3.1 pounds (1.4 kg)
• phentermine 7.5mg/topiramate 46 mg-- 17.8 pounds (8.1 kg)
• phentermine 15.0mg/topiramate 92 mg-- 22.4 pounds (10.2 kg)

The weight loss outcome in the highest dose group was approximately 10% of body weight--a significantly positive result in light of previous single agent trials.

One area of outcome caught my eye, the change in physiological and metabolic parameters over the course of the study.  Waist circumference decreased about an inch (2.4 cm) in the control group but three (7.6 cm) to three and one half inches (9.2 cm) in the low dose and high dose treatment group.  Blood lipid changes were also pretty impressive with LDL and triglycerides falling more in the treatment groups while good cholesterol values (HDL) increased more with the active drug combination.  Fasting insulin levels dropped significantly more in the active groups also.

Given historical problems with use of weight loss drugs, safety issues are important to monitor closely.  The most common adverse events in the active agent groups with rates higher than placebo were dry mouth (21%), paresthesias (numbness and tingling) (21%),  constipation (17%), dysguesia (10%), insomnia (10%), dizziness (10%), anxiety (4%) and irritability (3%).  Although infrequent (1%) depression was noted in the high dose group more than placebo.  One potential red flag with this combination was report of 11 cases of renolithiasis (kidney stones) in the high dose active agent group.

Topiramate inhibits the action of carbonic anhydrase.  This effect can cause decreases in serum bicarbonate and potassium as well as increasing risk of renolithiasis.  The rate of renolithiasis was lower in the low dose group suggesting a dose-related effect.  Additional, inhibitors of carbonic anhydrase have been noted to cause alterations in sensation (paresthesias) and in taste (dysguesia).

The authors note several relevant areas of caution.  Subjects with clinically relevant depression were excluded from the study due to concern about drug-induced depression.  Also some subjects noted cognitive adverse events, attention or memory problems, and this needs to be monitored in those more prone to such effects.  Additionally, the first application to approve this combination of phentermine and topiramate was turned down for lack of long-term cardiac safety data and data on risk of use during pregnancy.  This additional data is likely being collected for analysis and possible re-application given the impressive level of weight loss associated with this combination.

Molecular model of topiramate from Wikipedia Creative Commons, Author fvasconcellos.

Kishore M Gadde, David B Allison, Donna H Ryan, Craig A Peterson, Barbara Troupin, Michael L Schwiers, Wesley W Day (2011). Eff ects of low-dose, controlled-release, phentermine plus
topiramate combination on weight and associated
comorbidities in overweight and obese adults (CONQUER):
a randomised, placebo-controlled, phase 3 trial Lancet : 10.1016/S0140- 6736(11)60205-5

Fluoxetine (Prozac) Boosts Motor Recovery After Stroke

Antidepressant drugs are being used for multiple non-depression indications including chronic pain, peripheral neuropathy, migraine prophylaxis, irritable bowel syndrome, hot flashes, premature ejaculation and insomnia (list not inclusive).   I had previously posted results of research looking at the effect of antidepressants after stroke on cognitive recovery.  This study from the University of Iowa College of Medicine, Department of Psychiatry found that escitalopram was linked to improved cognitive recovery following stroke compared to placebo.

Now on a related note, a study has been randomized placebo controlled study of fluoxetine has been published looking at recovery of motor function following acute ischemic stroke.   Here are the key elements of the design of this study:

• Subjects:  113 patients with acute ischemic stroke ages 18-85 suffering hemiplegia or hemiparesis
• Baseline motor deficit: Fugl-Meyer motor scale (FMMS) score of 55 or less
• Intervention: Fluoxetine 20 mg daily for 3 months or placebo
• Key outcome measure: FMMS score at day 90

The raters on the key outcome measure were blinded to the assigned treatment.  The findings from the study were impressive—mean (standard deviation) FMSS scores for the fluoxetine group was 54(28) compared to only 35.1 (22) in the placebo group.  As might be expected, rates of post-stroke depression were lower in the fluoxetine group (7% vs 29%).    Adverse events included nausea and diarrhea in the fluoxetine group—a typical selective serotonin reuptake inhibitor side effect.  One subject in each group died during the follow up period.  More patients in the fluoxetine group were more independent suggesting that motor recovery is an important contributor to global function after stroke.  The motor recovery effect appeared independent of lower depression rates in the fluoxetine group.

So why would a drug used typically for depression potentially have a role in post-stroke motor recovery?  The authors note animal studies have shown that drugs affecting brain neurotransmitters can modulate the rate and extent of recovery following brain injury.   Rats given fluoxetine after ischemic brain injury appear to have enhanced hippocampal neurogenesis.  These studies support a potential role for selective serotonin reuptake inhibitors like fluoxetine to have a neuroplasticity effect that may aid brain healing from a variety of insults.  This is not a magic bullet—it appears necessary to pair the drug treatment with active rehabilitation efforts.   But when used together, the combination appears to result in a better motor recovery after stroke.  I think we are likely to see more active research in this area and search for novel neuroprotective compounds that my provide better outcomes for stroke and other brain injury patients. 


Molecular model of fluoxetine molecule from Wikipedia Creative Commons, author Benjah-bmmj27.

Chollet F, Tardy J, Albucher JF, Thalamas C, Berard E, Lamy C, Bejot Y, Deltour S, Jaillard A, Niclot P, Guillon B, Moulin T, Marque P, Pariente J, Arnaud C, & Loubinoux I (2011). Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet neurology, 10 (2), 123-30 PMID: 21216670