Benodiazepines -- a misunderstood drug family

Dr. Philip Grossi
Thursday, 13 August 2015

For many years I have believed that the benzodiazepines (diazepam, lorazepam, alprozolam, clonazepam etc.) are a much maligned and poorly understood family of drugs. This misunderstanding includes doctors, patients, and the government. My conclusion is based on many contacts with other doctors, many articles in the medical literature, and the thinking behind federal government's decision to exclude them as a benefit under Part D of Medicare. That last has been changed and they are now included as a benefit of Part D.

The misunderstanding has been perpetuated by a recent article in JAMA Psychiatry  by Moore and colleagues. They questioned their clinical usefullness, emphasized their addictive potential, and suggested much tighter control of their usage. They demonstrated complete tunnel vision because they failed to take into account the issues set out in the following paragraphs.

All benzodiazepines have four actions. Those are: anti-anxiety, antispasmotic, anticonvulsant, and soporific (sleeper). They are also useful in a variety of medical procedures and as a tool in alcohol withdrawal.   The indication found in the PDR or in online sites reflects a marketing decision by the manufacturing drug company. The manufacturing company decides to study a drug for a particular purpose and if the studies confirm its effectiveness and safety in the eyes of the FDA, then the FDA allows the company to promote the drug to the medical community for that purpose. The drug can be used for other purposes but it cannot be promoted for those other purposes. A good example of this is the study of clonazepam as an anti-convulsant for which it received an approval.  The vast majority of its usage however is as an anti-anxiety agent. The company did this because it already had diazepam (Valium) which was a massive product in the anti-anxiety space and it did not want to introduce a competing product.

Benzodiazepines are an effective pharmacological treatment for anxiety disorders.  Offidani published a meta-analysis of studies comparing benzodiazepines and antidepressants in Psychotherapy and Psychosomatics. The benzodiazepines showed superior efficacy and a more benign side effect profile. Furthermore, the discontinuation rate is much higher with the antidepressants.

Moore et. al. and the majority of the medical community are over-focused on dependency, addiction, toxicity, abuse, tolerance, and withdrawal syndromes. I have found that the rate of abuse is relatively low provided that the drugs are not given to alcoholics or individuals without anxiety disorders. People with anxiety disorders do not get addicted if the drugs are used properly. Antidepressants sometimes have very prominent withdrawal syndromes which can last weeks and are very uncomfortable. With regard to tolerance, this can definitely become an issue especially if these agents are need for a long period. There are a variety of strategies to prolong their clinical effect without raising the dose beyond acceptable limits. Contrary to popular opinion, these agents can be used for long periods with proper management and caution.

Some other oft expressed concerns include falls in the elderly, auto accidents, dementia, confusion, memory problems. While there is some merit in these concerns, if we compare these possible adverse events with those of the antidepressants and antipsychotics, the benzodiazepines look relatively better and less problematic in the long run. On the positive side of the ledger, these drugs enable individuals to relax, reduce anxiety, facilitate sleep and thus provide a better environment to work on longer term solutions to underlying problems.



Pediatric Bipolar Disorder vs ADHD

Dr. Philip Grossi
Thursday, 07 May 2015

One of the most common questions that arise in the office involves distinguishing between juvenile bipolar disorder and ADHD. Contributing to the difficulty is the finding that BPD and ADHD are co-morbid at least 50% of the time, i.e., those individuals meet criteria for both disorders. A further difficulty in drawing the distinction is that they are clinical diagnoses so by definition there is no test, scale, laboratory test or scan which precisely diagnoses the disorders.

There are historical and clinical characteristics that help to distinguish the two disorders. From a family history standpoint, children of parents who have BD are 13 times more likely to have BD than controls and twice as likely to have anxiety disorders as controls.  From a clinical standpoint adolescents with BD tend to display shifts in energy level from high to low or vice versa. Moods accompanying these energy shifts range from silliness, meddlesomeness, intrusive behavior, elation, expansive, belligerent, angry,and irritable, to sadness, gloominess, depression, and suicidal preoccupation. Other features may include decreased need for sleep, increased talkativeness, and the sense that the child's thoughts are racing, increased destructibility, and increased in work out put and risk taking behaviors.

When comparing patients with ADHD to those with BD those with BD had more mood elevation, grandiosity, racing thoughts, decreased need for sleep and hypersexuality. Both groups shared hyperactivity, distractibillity, pressured speech. and irritability. These were thus not helpful in making the distinction.

ADHD is found in 6-7% of US children with a greater prevalence in boys than girls. BD is equally distributed in girls and boys. If one takes a cohort of 100 5 year olds who meet the criteria for ADHD and they are reassessed every year, when they reach 25 years of age only 66 % continue to meet criteria, the other 34 % fall out of the category.  Those that continue to meet criteria at 25 will likely have the symptoms the rest of their lives. About 80% of children who meet criteria for ADHD meet criteria for at least one other disorder including learning disabilities, anxiety disorders, depression, and bipolar disorder. Children with ADHD have a low frustration tolerance which leads to aggressive behavior and anger episodes. In BD anger episodes and aggressive behavior arises out of irritable mood. While ADHD and BD can overlap, they each have some distinguishing features described above

There are some additional clinical findings found in BD children.  Those include marked irritability, oppositional behavior, frequent mood swings, distractability, hyperactivity, impulsivity, restlessness, giddiness or goofiness, racing thoughts, aggressive behavior, grandiosity, carbohydrate cravings, depressed mood, exhaustion, low self-esteem,  trouble getting up in the morning, and marked sensitivity to environmental stimuli and separation anxiety. Other symptoms somewhat less common include bed-wetting, night terrors, pressured speech, obsessional behavior, compulsive behavior, tics, learning disabilities, poor short term memory, poor organization, fascination with blood and guts, hypersexuality, manipulative behavior, bossy or bullying behavior, lying, suicidal thoughts, destructiveness, paranoia, and hallucinations and delusions.






Dr. Philip Grossi
Thursday, 30 April 2015

The connection between humans and their dogs is fascinating and intriguing. I have many patients who are extraordinarily attached to their dogs, spend large sums of money on sick dogs, rejoice at their unconditional love and affection, and mourn when they die. How did dogs come to occupy this trusted friendship and powerful social attachment.

Dogs respond to pointing cues to find hidden food or other rewards. There are other social cues that dogs respond to such as gaze direction to which children also respond. Both children and dogs interpret eye contact as communication suggesting a similar or shared cognitive style.

What explains these human-like attributes in dogs? Genetic studies have established that dogs evolved from wolves; but, wolves do not seek human assistance in solving problems nor so they attend to social cues as dogs do. Since the dog's human-like tendencies do not appear to be genetic in origin, possibly they were shaped by domestication, i.e., selection based on temperament which allowed dogs to interact with humans like partners. If this is the case, then there should be underlying biological processes which support this social and cognitive evolutionary convergence.

In a prior blog I talked about the important  role of oxytocin, a nonapeptide neuropeptide, in social interactions and formation of bonds between members of the same species. Can it also produce these effects in members of separate species? T. Romero and J. Oliva have studied the effect of administered oxytocin on dogs relative to other dogs and on the effect on dogs attending to human social cues. The results showed an increase in social contact between dogs, more social contact with humans, and more attendance to human social cues.  Could this suggest that increased oxytocin in dogs leads to an increased oxytocin response in humans?  Such a finding would suggest a dynamic similar to that found in a mother-infant bond.

Now comes Miho Nagasawa et. al. whose recent article in Science described an experiment in which the researchers watched 30 dog owners interacting with their dogs (varying breeds and ages) and measured the changes in urinary oxytocin before and after they interacted. The dogs that looked at their owners longest had the largest changes in urinary oxytocin. Their owners experienced a similar response. They could not replicate this with wolves. This supports the feedback loop described above and suggests that is transmitted partly by sustained eye contact between dog and human. 

Is the relationship one of cause and effect?  Nagasawa then administered oxytocin to another group of dogs before they interacted with their owners. They found an increase in mutual gaze between dog and owner. Strikingly they also observed an increase in oxytocin in the dog owners mediated by increase mutual gaze. This occurred in female dogs only.

These findings mirror findings in humans described by O. Weisman Nagasawa's results suggest that dogs have piggybacked on our parental behavior  such as staring into our eyes to produce rewarding caretaking behavior. This phenomena is bidirectional and so dogs experience reward as well. These behaviors convey selective advantage with regard to human preferences. It appears that we are tuned into dogs in a similar way we are tuned into children. Our relationship to dogs thus appears to be based on human bonding pathways.