Brain Posts Cracks Technorati Top Ten: Thanks!

I try to minimize self-promotion on this blog but today I'm going to do a little of that.  I started this blog nearly two years ago for personal motivation to stay current with research in the clinical neurosciences.  Blogging about recent research in clinical neuroscience kept me scanning PubMed abstracts directed to my Google Reader and kept me focused on succinctly summarizing work I felt was important.  Additionally, as I approach the end of my career, I felt a non-commercial blog might be a way give something back to my profession that has given so much to me.

Like many bloggers I follow my page views to see topics that might track more than typical interest.  I follow some of the blog ranking sites to gain perspective on Brain Posts.  This last week I was pleased to see that the Technorati algorithm ranked Brain Posts as the tenth ranked blog in the Family category and 40th in the Health category.  Technorati follows over 14,000 blogs in the Family category and over 15,000 blogs in the Health category.  I am very humbled and flattered by this recognition.

I don't understand the ranking algorithms (or their validity).  The numbers seem to jump around quickly and frequently.  But I do know that followers accessing the site and referencing the site play a key role in the rankings.  So this is really a post to thank those of you who have been visitors, commenters and post links to the site.

I plan to continue posting on clinical neuroscience research topics over the next year.  Additionally, I will be putting together some of the posts into electronic book formats.  This will involve selecting posts that might be of interest to specific reader groups.  Look for compilations of Brain Posts into eBooks formats under some of the following titles:

• Brain Science for Physicians
• Brain Science for Parents
• Brain Science for Teachers

Thanks again to all!

Vilazodone: A Novel Antidepressant

Vilazodone was approved by the Food and Drug Administration in the U.S. earlier this year, but is just now becoming available in pharmacies for prescription use.  The drug is marketed in the U.S. under the trade name Viibyd.  It is novel in that it the only antidepressant that combines two mechanisms that can increase serotonin in the brain cortex: selective serotonin reuptake inhibition and partial agonism of the 5HT1A receptor.  There are multiple selective serotonin reuptake inhibitors, i.e. fluoxetine (Prozac), sertraline (Zoloft), and escitalopram (Lexapro).  

There are also compounds that have an agonistic effect on the 5HT1A receptor.  These include:
Antidepressants: trazodone, nefazodone
Antianxiety drugs: buspirone
Atypical antipsyhotics: aripiprazole, ziprasidone, clozapine, asenapine
Illicit drugs/compounds: MDMA (ecstasy), LSD, psylocybin, cannabidiol (cannabis)
Antimigraine compounds: ergotamine
Other compounds: yohimbine

The combination of SSRI and 5HT1A agonist effect may synergistically increase serotonergic transmission.  

Two published clinical trials on vilazodone are available on PubMed.  The table below summarizes some of the key findings from the two published trials.

The dose of vilazodone studied was 40 mg in both studies.  Because of the common occurrence of gastrointestinal side effects, doses are typically initiated at a smaller level and increased to 40 mg over the first week or so.  The pattern and prevalence of gastrointestinal side effects with vilazodone appears similar to levels seen in previous SSRI trials.  Although headache was commonly reported with vilazodone, the rate did not differ from the rate endorsed by placebo.  Dizziness, dry mouth, insomnia and abnormal dreaming were endorsed at a higher level with vilazodone but by less than 10% of the subjects.

Although vilazodone was statistically superior to placebo on almost all depression measures, it was not statistically superior in remission rates in the Kahn study.  This finding along with the relatively low absolute response rate of 27.3% in the vilazodone group is a little disappointing.

The response and remission rates found in these two studies were similar to SSRIs.  Head to head comparison with an SSRI would be informative to see if vilazdone has any effectiveness or adverse event superiority.  Sexual side effects are common with the SSRIs and the two randomized vilazodone studies reported no difference in sexual side effects between vilazodone and placebo.  Additionally, the Rickels study showed some evidence for anxiety symptom reduction.  Clinical trials examining the effectiveness of vilazodone for anxiety disorders will likely be soon completed.

Disclosure:  The author has no stock in the parent company of vilazodone (Forest Labs).  Additionally no honoraria or research grant support has been received related to this drug.  The author received no reimbursement for writing this post and the comments are entirely those of the author.

Information on the agonists for the 5HT1A receptor obtained from Wikipedia.

Chemical molecular structure of vilazodone from Creative Commons file at Wikepedia by author Meodipt.

Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, & Reed CR (2009). Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. The Journal of clinical psychiatry, 70 (3), 326-33 PMID: 19284933


Khan A, Cutler AJ, Kajdasz DK, Gallipoli S, Athanasiou M, Robinson DS, Whalen H, & Reed CR (2011). A randomized, double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder. The Journal of clinical psychiatry, 72 (4), 441-7 PMID: 21527122

Persistent Insomnia in Depression Responding to Antidepressants

Sleep problems commonly occur as part of a problem with mood disorders including depression.  Changes in sleep duration (insomnia or hypersomnia) are one of the criteria for the diagnosis of depression in the Diagnostic and Statistical Manual of Mental Disorders.  Although not absolutely required for the diagnosis, insomnia is a complaint in the the majority of subjects presenting for clinical trials in the treatment of depression.

The selective serotonin reuptake inhibitors (SSRIs) like fluoxetine (Prozac) have become one recommended strategy in the treatment of depression.  However, unlike other antidepressants, the SSRIs commonly do not have a sedative effect.  It is possible that when someone gets an antidepressant response to an SSRI, sleep disturbance also resolves.  However, in clinical practice, SSRIs commonly produce a partial remission of depression but fail to improve problems with insomnia.  So what does this type of response mean and what can be done for those with improvement in depression but residual sleep complaints.

Gulec and his research team from Turkey have some recent research on this topic posted online at the Journal of Affective Disorders.  They followed a group of adults with major depression treated naturalistically--i.e. treating psychiatrists could select the antidepressant drug although algorithms for dose and sequencing were followed.  Subjects were followed with research rating scales for a period of 52 weeks.  Some subjects responded and remained well.  Some subjects responded but had a recurrence of depression in the one year follow up period.  The key findings from the study:

• Persistent insomnia rates were high in those who had a recurrence of depression
• The recurrent groups showed the following rates of insomnia prior to recurrence: onset insomnia (difficult falling asleep) 58%, terminal insomnia (early morning awakening) 33% and middle of the night insomnia 8%.
• Only 26% of those subjects whose depression remained remitted throughout the 52 week follow up period endorsed any persistent insomnia complaint.

The authors note their study is consistent with other studies supporting insomnia as a marker for poor prognosis is depression.  Reynolds and colleagues found that subjects who remitted with an antidepressant drug (including improvement in subjective sleep) had had high rate of continued remission of depression with psychotherapy alone.  Those whose insomnia persisted were less likely to benefit from psychotherapy alone as a long term maintenance strategy.


So an important question is what to do when insomnia persists despite a general antidepressant response.  It appears this is a problem that is too important to ignore and hope it goes away.  Options appear to include adding a sedative antidepressant, switching to another antidepressant, adding a sedative hypnotic treatment for insomnia or adding cognitive behavioral treatment for insomnia.  Here there is little data to support one of these choices over the others.  A research study examining these types of options is needed to aid patients and their clinicians in the management of this common clinical situation.

Photo of Moth Hovering Over Flower Courtesy of Tim Yates

Gulec M, Selvi Y, Boysan M, Aydin A, Besiroglu L, & Agargun MY (2011). Ongoing or re-emerging subjective insomnia symptoms after full/partial remission or recovery of major depressive disorder mainly with the selective serotonin reuptake inhibitors and risk of relapse or recurrence: A 52-week follow-up study. Journal of affective disorders PMID: 21684011

Reynolds CF 3rd, Frank E, Houck PR, Mazumdar S, Dew MA, Cornes C, Buysse DJ, Begley A, & Kupfer DJ (1997). Which elderly patients with remitted depression remain well with continued interpersonal psychotherapy after discontinuation of antidepressant medication? The American journal of psychiatry, 154 (7), 958-62 PMID: 9210746

Brain Basis for Emotion Recognition Deficits in Depression

There is a emerging understanding of the role of social perception problems in depression and anxiety disorders.  Depression appears to effect the cognitive ability to judge the facial expression of others.  This impairment poses a challenge for interpersonal function and social relationships.  Research is now pinning down the neural basis for this deficit and to determine it’s persistence and the effect of depression remission on this social cognition function.

van Wingen and colleagues from the Netherlands recently published an fMRI study on this topic in Psychological Medicine.  The study had the following elements in research design:

• Subjects: Twenty case subjects with first episode of major depression (medication naive), Twenty one case subjects recovered from a first episode of depression and 30 healthy individuals without a history of depression
• f MRI Task: Visual recognition of anger or fearful face by semantic labelling or visual matching compared to a control task of matching facial orientation without attention to emotion
• Additional Neuropsychological Testing: Depression symptom level, anxiety (state and trait) symptom level, IQ, memory, visual learning, attention, psychomotor speed and executive function.

The depression case subjects were not different from recovered depressed subjects and controls on most of the tests of neuropsychological function.  As expected, they did have higher depression symptom severity scores (Hamilton Depression Scale average for the depressed group was 21.8) and higher anxiety symptom severity scores.

The depressed group performed as well as the remitted group on the control task and the visual emotion matching task.  However, they performed worse than both groups on the semantic matching task, i.e. selecting the correct word label for the emotion displayed visually.  

The brain regions that correlated (increased activation) with impaired semantic emotion labeling included three distinct regions:

• right amygdala
• left inferior frontal gyrus
• anterior cingulate cortex

The authors propose that one explanation for this finding in three distinct brain regions.

“The left inferior frontal gyrus is thought to integrate language with other information (Hagoort, 2005;Willems et al. 2007). Therefore, we suggest that the inferior frontal gyrus may integrate the semantic knowledge about the concepts of anger and fear with the emotional information conveyed by the faces by interacting with the amygdala. The concurrent activation of these systems may subsequently trigger automatic negative thoughts and stimulate task unrelated processes such as rumination (Siegle et al. 2002; Ray et al. 2005), and thereby hinder task appropriate behaviour.”

This explanation fits with the cognitive behavioral theory of depression.  The core concept being that depression is characterized by increased automatic negative thoughts about the self, the future and the environment.  The thoughts are generated by a maladaptive negative cognitive schema.  Activation of these automatic thoughts (i.e. by being shown negative facial emotions) produces distraction from tasks (i.e. correctly labelling these facial emotions). This process appears limited to when depression is present as the recovered depression group showed no deficit.

The authors also conclude the findings could be due to a compensatory mechanism for inadequate behavior or an altered coping mechanism for dealing with demanding situations. 

This study provides additional support that fMRI research may lead to advances in the treatment of depression by both psychotherapy and psychopharmacologic interventions.

Screen shot of 3D Brain showing the limbic system structures amygdala and cingulate cortex (along with the inferior frontal cortex) thought to be involved in impaired facial recogniton in depression.

van Wingen, G., van Eijndhoven, P., Tendolkar, I., Buitelaar, J., Verkes, R., & Fernández, G. (2010). Neural basis of emotion recognition deficits in first-episode major depression Psychological Medicine, 41 (07), 1397-1405 DOI: 10.1017/S0033291710002084

Limiting Debt May Be Good For Your Mental Health

Article first published as Limiting Debt May Be Good For Your Mental Health on Technorati.

The relationship between financial status and risk for medical and mental disorders is complex. Premorbid functioning (level of function prior to the onset of a condition) may influence cognitive performance, motivation and the social interaction skills necessary for gaining employment and career success. Failure to obtain (or maintain) a rewarding job can contribute to increased stress and possible reduced access to treatment for medical or mental health conditions. Two recent studies examined the relationship between financial factors and risk for mental disorders. These studies provide potential strategies for the prevention of some common clinical neuroscience conditions.

Jenkins and colleagues in the United Kingdom studied the relationship between a variety of economic indicators and risk for presence of a mental disorder in over 8000 individuals in England, Scotland and Wales. The previous well-documented association between lower socioeconomic status and increased risk for mental disorders was found in this research study. Risk for any mental disorder (neurotic disorder, psychotic disorder, alcohol or drug use disorder) ranged from 24% of the highest earners to over 40% for lowest income group in men. For women the difference was 18% for the highest income group compared to 33% for the lowest income group.

Examining the relationship between income and risk for mental disorder in more detail in this sample produced an interesting finding. Income was strongly associated with the number of debts and the number of debts strongly correlated with rates of mental disorders. When the presence of personal debt (and other socioeconomic factors) was controlled, the association of income and mental illness vanished or was greater reduced. A small effect for income on rates of neurosis persisted after controlling for number of debts.

The authors of this study note that it was a cross-sectional study and there was no ability to examine the sequence of events. Perhaps the primary association is that those with a mental disorder are more likely to take on debt (whether out of necessity or perhaps because of impaired financial decision making associated with cognitive limitations). But the authors do note an important implication of their research. The role of personal debt and risk of mental disorder is rarely studied. Personal debt levels are increasing in many countries around the world. The role of debt in risk of (and management) of mental disorders is an emerging public health issue.

A second abstract that caught my attention in this topic area is a study by Lang and colleagues in the UK and the U.S. They noted that the prevalence of common mental disorders tends to rise up through midlife when a peak rate is reached. Their study found this effect occurred only in the lowest income group. Those in higher income groups appeared to be protected from this midlife prevalence rate increase. There was no mention of the potential role of debt in this common epidemiological finding.

These findings have influenced how I assess and manage patients. I tend to be more likely to ask about personal debt levels and the influence of debt (and intrusive debt collectors) in mood, anxiety levels and personal distress. Using debt counseling resources and encouraging the limitation of personal debt may become more common important components of clinical neuroscience.

Photo of credit card from Creative Commons file at Wikipedia.

Jenkins R, Bhugra D, Bebbington P, Brugha T, Farrell M, Coid J, Fryers T, Weich S, Singleton N, & Meltzer H (2008). Debt, income and mental disorder in the general population. Psychological medicine, 38 (10), 1485-93 PMID: 18184442

Lang, I., Llewellyn, D., Hubbard, R., Langa, K., & Melzer, D. (2010). Income and the midlife peak in common mental disorder prevalence Psychological Medicine, 41 (07), 1365-1372 DOI: 10.1017/S0033291710002060

ADHD and the Athlete

Athletes are not spared from the risk of developmental disorders like learning disabilities and attention deficit hyperactivity disorder (ADHD).  Once an athlete is diagnosed with ADHD, the effect of this disorder and it's treatment on athletic performance becomes important.  

Dr. J. W. Parr recently published a comprehensive review of recent research and understanding of ADHD in the athlete.   The review includes a look at diagnostic issues as well as a summary of the neurobiology of ADHD.  After this general introduction, the review focuses on some key issues in athletes with ADHD.


Although some children with ADHD have motor performance problems the majority do not.  The effect of ADHD on athletic performance is somewhat related to individual sporting activity.  ADHD may be more of a sport performance problem in sports requiring prolonged attention, i.e. fencing and less of a problem in large muscle performance sports such as swimming and track and field.  Indeed, some of the world's most successful athletes have been diagnosed with ADHD.  Parr notes that multiple Olympic gold medal winner Michael Phelps has made it publicly known he has ADHD.


Additionally, Parr notes that ADHD appears to be as common in athletes as in the general population.  Using his unpublished observations of athletes at Texas A & M University, he estimates that 7 to 9% of all athletes are receiving stimulant and nonstimulant medications for ADHD.  Given the estimated community prevalence of ADHD at 4 to 7%, the prevalence of ADHD medication use in the Texas A & M athlete population suggests a prevalence at least as high as the general population.

Parr reviews the risk of substance abuse with stimulant medication.  He notes that the oral stimulant drugs in ADHD typically lack significant euphoric effects found with intravenous stimulant illicit drug use (i.e. cocaine or methamphetamine). 


There is increasing research examining the effect of ADHD stimulant drug use and performance.  Acute administration of methylphenidate or placebo to a group of cyclists (without ADHD) resulted in prolonged peak performance.   Whether chronic administration of stimulants in those with ADHD improves performance in unclear.  However, there is some data that supports a drop in motor performance in athletes with ADHD on days they skip or miss their ADHD medication.

Athletes commonly develop a pattern of dosing their medication in a manner that accommodates their sporting activity and perceived effects of medication on performance.  Parr notes this is somewhat of an individual decision.  He notes some baseball pitchers that always use their ADHD medications on days they are charting pitches but many do not take it before days they actually pitch.


Dr. Parr does not recommend routine EKG testing of athletes taking medication for ADHD.  He feels that there is no data to support an increased risk of cardiac death in athletes with ADHD on stimulant treatment.  However, he does note one area of medical concern with athletes using ADHD medications.  Some stimulants may impair thermoregulation and increase the risk of heat exhaustion or heat stroke.  He notes physicians and trainers should make sure to provide athletes with ADHD adequate hydration and increased surveillance for heat-related illness.

Many college athletes with ADHD are diagnosed at an early age.  Dr. Parr recommends all college level athletes receiving ADHD drugs submit a copy of the prescribing physicians assessment and treatment recommendations.  The NCAA recommends student athlete documentation in ADHD include:

• Comprehensive clinical evaluation
• Observations and results from ADHD rating scales
• Specific diagnosis
• Recommended treatment

Such prior documentation is necessary should an athlete test positive for a stimulant on urine drug testing.  Disclosure of stimulant use for medical reasons at the time of submitting a urine sample and prior documentation will be needed to address any positive urine drug test results.

This review of ADHD in the athlete is well-written and information for physicians, trainers and other medical staff working in a sports medicine setting.

Photo of 2011 Spring Training game between St. Louis Cardinals and Minnesota Twins in Jupiter, Florida courtesy of Yates photography. 

Parr JW (2011). Attention-deficit hyperactivity disorder and the athlete: new advances and understanding. Clinics in sports medicine, 30 (3), 591-610 PMID: 21658550

Mild Cognitive Impairment in the Elderly

 The presence of mild cognitive impairment (MCI) in elderly individuals is often a clinical challenge of uncertain prognostic value.  Defined as cognitive function below the normal range but insufficient for a diagnosis of dementia, MCI is receiving increased research attention.  This week in the New England Journal of Medicine, Dr. Ronald Petersen, a neurologist from the Mayo Clinic in Rochester, Minnesota highlighted what is known about MCI.  His review summarizes some of the recent research related to MCI as well as some issues in clinical assessment and management.

Dr. Petersen noted that MCI is typically separated into two categories.  The first is amnestic MCI where memory impairment is predominant.  The second is nonamnestic MCI where deficits in other domains such as language, attention or visuospatial function.

Prevalence (70-89 year old non-dementia sample)

• 11.1% amnestic MCI
• 4.9% nonamnestic MCI

Amnestic MCI may be harbinger of Alzheimer's disease

Nonamnestic MCI may be harbinger of frontotemperal lobe degeneration or dementia with Lewy bodies

Risk of dementia in elderly about 1% to 2% per year

Risk for those with MCI raised to 5% to 10% per year

Assessment

•     Brief Minimental Status Exam (MMSE) often insensitive to early impairment
•     Better tools include the Short Test of Mental Status and Montreal Cognitive Assessment
•     Comprehensive neuropsychological testing necessary for definitive diagnosis and severity rating

Mild cases may be due to depression or the cognitive effects of medication

Differentiating from dementia primarily by level of functional impairment

This may be assessed using the Functional Activities Questionnaire

Predictors of progression of amnestic MCI to dementia (primarily research tools at this point)

•     More severe MCI
•     Presence of the Apolipoprotein epsilon 4 gene
•     Hippocampal volume less than the 25%tile for age by magnetic resonance imaging
•     PET imaging shows temporal and parietal brain hypometabolism
•     Cerebrospinal fluid assay shows low beta amyloid 42 to tau protein ratio
•     Brain amyloid plaques on PET imaging using Pittsburgh compound B

Treatment--No medication approved by FDA for treatment of MCI

• Alzheimer's drugs donepezil, galantamine and rivastigmine have negative placebo-controled clinial trial results in MCI.  Donepezil but not Vitamin E reduced progression to Alzheimers disease in MCI in one trial for first two years but not at three years of treatment
• Some evidence that cognitive rehabilitation may be helpful in short term improvement of memory in MCI
• Treat reversible cardiovascular risk factors if they are present
• Encourage brisk walking exercise 150 minutes per week

Given that 15% of elderly individuals demonstrate a form of MCI, it is likely this condition will generate significant ongoing research interest.  An intervention that would reduce the risk of progression of dementia after the onset of MCI would be a major advance in the prevention of Alzheimer's Disease.

Dr. Petersen provides copies of the Short Test of Mental Status, the Montreal Cognitive Assessment and the Functional Activities Questionnaire in an online appendix to the review.  Readers who do not have access to the online New England Journal of Medicine can contact me for alternate options to receive copies of the instruments. 

Photo of PET scan of patient with Alzheimer's Disease showing reduced glucose metabolism in the temporal lobes courtesy of Wikipedia Commons file from the National Institute on Aging,  Alzheimer's Disease Education and Referral Center.   
 

Petersen, RC (2011). Mild Cognitive Impairment New Engl J Med, 364, 2227-2234

One Hundred Years Ago Today (June 13, 1911)

One hundred years ago today the United States was still three years away from the first of the world wars that would shape the nation forever.  In 1911, now 135 years old, the U.S. faced many challenges and opportunities.  

Looking back at 1911, U.S. historians would rank some of the most  important facts about 1911:

• U.S. unemployment was 7.6%
• A first class stamp was two cents
• Princeton University won the NCAA football championship (shared with Penn State University)
• British Physicist Edward Rutherford discovered the structure of the atom
• American Geneticist Thomas Morgan shows that inherited traits are related to genes located at specific sites along the chromosome

In the midwestern U.S., the state of Nebraska was only 44 years old after being granted statehood in 1867.  One extended family had already been settled in the state for nearly thirty years.  Attracted to the state by the U.S. Homestead Act signed into law by President Abraham Lincoln, this family migrated to Nebraska seeking opportunity and a better life.  The Homestead Act promised inexpensive land to those who settled on the land for five years, built a home and began raising crops.

What seemed a great opportunity, came with significant hardship.  Most of the best farm land was owned by the railroad companies.  Only the marginal farm land was open to the new settlers coming to the region.  Growing crops was not easy and the Nebraska winters were cold, the summers hot and often so dry that no crops were harvested.  Most of these Homestead Act immigrants found the challenge too difficult and they moved on.

But one family living near the Fillmore County town of Geneva, persisted and did not give up.  Maybe they were too stubborn to seek other opportunities.  But persist they did and this family planted, harvested, and had children. On this day 100 years ago today (6/13/1911) into this extended family was born a son named Theodore Robert.

Probably named after U.S. president (1901-1909) Theodore Roosevelt, Theodore Robert (Bob) grew up in a difficult time.  As a child, the challenges of World War I made all Americans sacrifice.  As a young man, growing up during the Great Depression made finding a job difficult.  But despite the challenges Bob fell in love and married a young women named Florence.  With limited opportunities in Nebraska, Bob, his young wife and their infant daughter Shirley moved to California. 

Bob was later urged by his Nebraska family to return and be the principal farmer of the Yates homestead farm.  He agreed and returned to Nebraska despite a growing income and opportunity in the California citrus industry.

Back in Nebraska, he farmed the land, raised award-winning corn and started a successful beef cattle business.  He and Florence had a second child named William Robert.  

That second child born to Bob and Florence was me, William Robert Yates.  I am so fortunate to be the son of a such a kind and hard working man as Bob Yates.  I am fortunate to have had a father who cherished his family and his faith.  I am proud of my parents and the Yates family that took on the challenge to move to Nebraska and then flourished through difficult times.

Today, Brain Posts takes a break from commentary on clinical neuroscience research. Today is a day I remember my father (pictured above) born 100 years ago today.  Dad, Shirley and I love you so very much.  Although you have been gone for over 40 years, the Yates family lives on and we all strive to live up to the example of your life.

Photo above of Bob Yates watching as his corn wins highest yield competition courtesy of Yates Photography.  Photo below of me and my parents Bob and Florence Yates also courtesy of Yates Photography.  

Source for historical information on 1911 from Wikipedia. 

Smokers Display Abnormal Amygdala Responses to Fear

Mechanisms underlying the risk for developing and maintaining an addiction continue to be poorly understood.  Nicotine dependence appears to share many of the characteristics of other drugs of addiction.  Heavy smokers are more likely to abuse alcohol and other drugs.  They are also more likely to have a parent with an alcohol or drug abuse diagnosis.  Understanding the mechanisms of nicotine dependence may provide insight into other drugs of abuse.

A study from Oezuer Onur from the University of Bonn in Germany and his German colleagues provides some interesting new findings related to the brain in smokers.

In this study, smokers were compared to non-smokers on a face perception task.  Smokers were scanned twice.  One scan occurred quickly after smoking (satiety state) and a second scan occurred in the morning after a period of abstinence from nicotine overnight.  In the second situation, smokers were reporting some withdrawal symptoms including urges to smoke a cigarette.

Smokers in the satiety state were identical to nonsmokers in their amygdala response to faces.  However, smokers after a night of abstinence showed a significantly lower response to fearful faces.  This effect was mapped to the amygdala and more specifically the basolateral region of the amygdala. 

The authors note that their study supports a "fear-selective malfunction of the amygdala while craving nicotine versus while being satiated".   The authors note this finding is likely due to one of two explanations:

• The changes reflect the consequences of addiction or
• The changes reflect a pre-existing (pre-smoking) vulnerability

Distinguishing between these two causes should be fairly straight forward.  One method would be to examine a group of non-smoking adolescents or young adults who do not smoke but are the offspring of smokers.  Another strategy might be to follow a group of smokers willing to stop smoking who display this amygdala fear abnormality and scan them over an extended period of time as they continue to be abstinent.

The authors suggest that impaired fear reactivity in smokers might have clinical implications.  Smokers may be less likely to respond to fear as a motivating factor in personal and public health efforts to quit smoking.  They also report that the amygdala compensation when nicotine levels are high might contribute to positive re-inforcement through "psychoactive and procognitive effects".

Understanding the effect of smoking and acute nicotine withdrawal may provide better understanding of the effects of current smoking cessation drugs and also provide insight into new drug development.

Brain screen shot from 3D Brain showing the amygdala in blue from the author's files.

Onur OA, Patin A, Mihov Y, Buecher B, Stoffel-Wagner B, Schlaepfer TE, Walter H, Maier W, & Hurlemann R (2011). Overnight deprivation from smoking disrupts amygdala responses to fear. Human brain mapping PMID: 21618661

Age-Specific Psychotic Effects with Cannabis Use

There is increasing evidence that some users of cannabis may be vulnerable to adverse cognitive effects including psychotic symptoms. Many adult casual users of cannabis appear to have minimal cognitive effects. However, younger users and those with underlying mood or psychotic disorders may experience significant adverse consequences of regular and heavy cannabis abuse. A previous post linking cannabis-related psychosis to family history of psychosis is posted here.

Schubart and colleagues in the Netherlands and UCLA recently analyzed the rates of reporting psychotic experiences in European (primarily Dutch-speaking)adolescents and young adults. They looked specifically for the rates of endorsement of psychotic and mood symptoms in adolescents grouped by frequency and quantity of cannabis use.
Psychotic symptom experience is commonly grouped into what are known as positive symptoms or negative symptoms. Positive symptoms of psychosis typically include delusions, auditory hallucinations and visual hallucinations. Negative symptoms of psychosis typically include loss of motivation, withdrawal, and lack of goal directed productivity.

Over 17,000 young adults participated in the survey with over two thirds of the respondents being classified as users. Looking at the entire group of regular cannabis users, their scores on measures of psychosis and depressive symptoms did not differ from those who reported not using cannabis.

However, two factors among the users identified subgroups with signficant endorsement of symptoms of psychopathology:

• Cannabis users who initiated use before the age of 12 were three times more likely than non-users to be in the top 10% of scores on psychotic positive symptoms
• Regular heavy cannabis users (greater than 25 euros spent per week on cannabis) were 2.8 to 3.4 times more likely to be in the top 10% of scorers on scales of positive and negative psychotic symptoms as well as depressive symptoms.

The authors noted in the discussion that this cross-sectional design can not prove a causal pathway. It is possible that young people with psychotic symptoms may be more likely to begin using cannabis. Additionally, they note that young age of onset of cannabis use may also indicate a larger cumulative exposure that could be related to psychotic and mood symptoms.

However, they do note their findings are consistent with the possibility that tetrahydrocannabinol (or other cannabis drugs)may have increased toxicity "during critical phases of brain maturation". There may be a window of vulnerability to the effcts of cannabis. Use after passing through this window, limited cannabis use may have limited cognitive effect. Early cannabis use and heavy chronic use may be a much different story. 

Photo of a black and yellow argiope spider from North Palm Beach Florida courtesy of Yates Photography.

Schubart CD, van Gastel WA, Breetvelt EJ, Beetz SL, Ophoff RA, Sommer IE, Kahn RS, & Boks MP (2010). Cannabis use at a young age is associated with psychotic experiences. Psychological medicine, 1-10 PMID: 20925969

Bupropion Fails to Aid Hospitalized Smokers with Heart Disease

Smoking and nicotine dependence increase rates for heart disease in the general population. Among those with heart disease, continued smoking increases mortality rates. Targeting smoking cessation efforts at those with heart disease (secondary prevention)is an important clinical challenge.
 

Most of the research data related to drugs for smoking cessation come from subjects recruited from the general population. Both bupropion (Zyban)and varenicline (Chantix)are FDA-approved drugs for smoking cessation in the United States. There is limited data of the safety and effectiveness of these two compounds in those with heart disease.

Dr. David Planer and colleagues from Israel recently published a randomized clinical trial of smokers admitted to the hospital with acute coronary syndrome (myocardial infarction or unstable angina). Subjects in this study were required to have the intent to stop smoking. Subjects received either placebo or bupropion sustained release 300 mg daily. All subjects also received five sessions of smoking cessation counseling from a nurse or physician. These counselors had some previous experience in smoking cessation and received additional training from a smoking cessation counselor prior to the trial.

Unexpectedly, bupropion failed to provide an additional increase in abstinece compared to placebo with the following rates noted at several study time points (Bupropion Bold followed by (Placebo) rates:

• 3 months: 44% (43%)
• 6 months: 37% (42%)
• 12 months: 31% (33%) 

What is striking about these outcome comparisons in the rate of placebo response. The authors note nicotine dependence has one of the lowest rates of placebo response with studies commonly reporting placebo response rates as low as 10% at one year. It is possible that the effect of physician or nurse directed counseling at the time of hospitalization (when motivation may be highest)is quite powerful. This may be the most important finding from the study and provide impetus for more wide spread adoption of this strategy in clinical settings.

Interestingly, one predictor of smoking cessation at one year in this study was undergoing a cardiac procedure (angiography or coronary artery bypass graft) during the hospitalization (odds ratio 4.2, p value=.02). The authors hypothesize that undergoing an invasive procedure may potentiate the psychological distress of the hospitalization and increase motivation for smoking cessation to limit the risk of future procedures and hospitalizations. Previous outcome studies in alcoholism have found that a serious medical problem related to drinking (and the need to be abstinent to address this medical problem) is one of the strongest predictors of alcohol abstinence.

I think this study can not be interpreted to mean there is no place for bupropion in smoking cessation in those hospitalized with coronary artery disease. Coronary artery disease patients hospitalized in facilities with smoking cessation counseling resources may be better off with initiaion of bupropion or another smoking cessation drug. The study did find bupropion to be safe and generally well tolerated in this population. Bupropion might be a reasonable choice for smokers who experience depression in the course of the heart disease.

Physicians should see this study as an example of the power of their words and efforts in smoking cessation. Strongly urging smoking cessation in a place and time where it is most likely to be effective is crucial. Missing such opportunities may contribute to continued progression of heart disease and other smoking-related medical problems.

Photo of Cattle Egret from Maui Hawaii Courtesy of Yates Photography
Planer, D., Lev, I., Elitzur, Y., Sharon, N., Ouzan, E., Pugatsch, T., Chasid, M., Rom, M., & Lotan, C. (2011). Bupropion for Smoking Cessation in Patients With Acute Coronary Syndrome Archives of Internal Medicine DOI: 10.1001/archinternmed.2011.72