Dr. Grossi's Blog
Robert Gibbons and John Mann published a meta-analysis of seventeen randomized, placebo-controlled studies involving 8,027 participants. They reported that varenicline (Chantix) improved tobacco abstinent rates when compared to placebo and buproprion (Wellbutrin). They also reported that valenicline was not associated with adverse psychiatric events, i.e., there was no greater incidence of depression, agitation, mood problems, or suicidal ideation in those treated with varenicline than those on placebo. The authors also evaluated a large data set from DOD involving 35,000 smokers. In this study in both the overall sample and the portion who had comorbid psychiatric diagnoses the smokers who received valenicline were awarded fewer diagnoses of psychiatric disorder than those who received nicotine replacement therapy. There is not evidence in these studies of new or emerging psychiatric symptoms.
In 2009 the U.S. Food and Drug Administration placed a black box warning for varenicline regarding adverse psychiatric events. This has placed clinicians in the unenviable position of proving a negative. i.e., psychiatric symptoms are not associated with the medication. The initial trials run by Pfizer, the manufacturer, to seek approval from the FDA excluded participants with a psychiatric diagnosis. After the drug was released and used in the community, depression, anxiety, mood disorders, and suicidal ideation and action were observed and the drug was blamed and the press sensationalized and inflated the adverse effects leading to caution on the part of prescribers. Had the initial trials not excluded those with a psychiatric diagnosis, then they could have been evaluated with a control group.
As a clinician I am always balancing the risks, continuing smoking, with the benefits, decreased mortality from many causes. The risk is high and the benefit is substantial. The data are clear. A large proportion of smokers who want to quit and use pharmacological cessation aids can quit and psychiatric symptoms remain relatively stable during and after quitting. I advise that any increase in anxiety, depression, irritability etc. are transient and mild. I do advise them to expect nausea and vivid dreams which I treat if troublesome.
In the January 2014 issue of the American Journal of Psychiatry, Mark H. Pollack, M.D. et.al. published an article about augmentation and switch strategies for social anxiety disorder. Initially 397 participants received sertraline (Zoloft). Of that number 181 were nonresponders and were randomly assigned to one of three groups: sertraline plus clonazepam, switch to venlafaxine (Effexor), or sertraline plus placebo. At the termination of the study they found that the sertraline plus clonazepam group showed a greater improvement than the other two groups. The study authors conclude "the findings suggest that the clonazepam augmentation strategy provides relative benefits for sertraline nonresponders with social anxiety disorder."
I am highlighting this study because it is the first clinical trial data using benzodiazepines as an augmentation of SSRIs in anxiety disorder patients. This is surprising in light of the fact that this strategy is very likely the most common strategy used by practicing psychiatrists. It is important to convert the practice based strategy into one that is based on clinical trial data for many reasons including that it can now be incorporated into practice algorithms which will become more common in future evidence-based practice. I am also using this article as a bridge to issues regarding the use of benzodiazepines which are among the most commonly misunderstood drugs in all of medicine. This family of drugs includes widely used drugs such as clonazepam (Klonopin), alprazolam (Xanax), diazepam (Valium), and lorazepam (Ativan). All drugs in this family have four actions: anti-anxiety, anti-convulsant, anti-spasmotic, and soporific (sleeping agent). The PDR indication for the drugs' use is essentially a marketing decision by the pharmaceutical manufacturer. Roche the manufacturer of clonazepam studied clonazepam as an anti-seizure medication and the FDA approved it for use as an anti-convulsant. It took years for its value as an anti-anxiety agent to be appreciated.
The benzodiazepines have been available since the 1960s. They were initially embraced because they were much safer than other drugs in wide use such as the barbituates and older sedative hypnotics. Adverse effects such as addiction, cognitive side effects, amnestic behavior etc. were publicized in the 1970s and the drugs fell out of favor until about 1982 with the publication of an article demonstrating the effectiveness of alprazolam in panic disorder. Many doctors are still focused on these negative effects and do no believe that the drugs impact the core problem in anxiety. This belief is not supported by the Pollack article cited above because many core symptoms were measured in that study and the change in symptoms was tracked with the Liebowitz Social Anxiety scale.
I believe the evidence supports my belief that the benzodiazepines are extraordinarily effective and safe agents. In the many thousands of patients I have treated with these drugs, I have yet to get anyone addicted or experience any major adverse event. It is certainly true that they should almost never be used in individuals with an alcohol problem, should be used carefully in the elderly, cognitive side effects should be monitored, and doses kept to reasonable but effective limits which implies that a strategy be employed to handle tolerance which is common with all members of this drug family.
Recently I saw a very lonely freshman college student who had come to the Bay Area from another state leaving family and high school friends behind to make her way in a new social ecosystem. That experience got me thinking about a number of papers I had read about loneliness over especially the last ten years. The first paper I read about social isolation and its effects on mortality was in the Science in the late 1980s. Following that were a steady stream of papers documenting the unhealthy changes in cardiovascular, immune, and nervous system which is undoubtedly related to the reduction in life expectancy of lonely people. I should add that it is not the number of social contacts that is important but the subjective experience of loneliness. Feeling alone and being alone are not identical concepts. Some people are socially isolated but don't feel lonely.
Lonely people tend to show changes in physiology, e.g., higher vascular tone leading to increased resistance to blood flow and thus imposing an added burden to cardiac function. They also tend to have higher cortisol and epinephrine levels in urine and saliva. These are signs of an overly active sympathetic nervous system. From an evolutionary standpoint this makes good sense because it signals that the social ties to the tribe are too weak and thus one's genetic contribution is in danger (decreased fitness) because the individual has abandoned the protection of the group. So it's an aversive signal that will increase the chances of passing on the individual's genes (increased fitness). So it's adaptive in the short term but unhealthy over the long term.
Several papers from geneticists at UCLA have demonstrated increased activity of a number of genes promoting inflammation and decreased activity of genes that retard inflammation and thus cardiovascular disease associated with inflammation. Genes affecting the immune system are also suppressed leading to increased susceptibility to viral infections.
Loneliness also has an effect on sleep. Lonely people sleep a normal number of hours but tend to awaken unrest-ed and fatigued. They also get less enjoyment from leisure activities. Social psychologists have characterized lonely people's view of social interactions as negative and their view of others as negative. They pay more attention to negative social cues than others do. As with other mental states, certain researchers are using MRIs and other tools to tie a specific brain region to the feeling. In this case the ventral striatum was found to be less active.
In the 2008 book, Loneliness: Human Nature and the Need for Social Connection, John Cacioppo, the author and a social psychologist at the University of Chicago, postulated that there is a "genetic thermostat" for loneliness that has different set points in different people. He further states, "You're not inheriting loneliness; you're inheriting how painful it feels to be alone."
How does this inform me about treating patients such as the abovementioned college freshman? It leads to specific advice about lifestyle choices and further to challenge the negative view of social situations with alternative explanations which over time should result in a more positive experience.