Dr. Philip Grossi
Tuesday, 06 November 2012

In the September 2012 issue of the American Journal of Psychiatry Karen Ersche, PhD, et al. published an article entitled "Cognitive Dysfunction and Anxious-Impulsive Personality Traits Are Endophenotypes for Drug Dependence". Most readers are probably not familiar with the term endophenotype. The authors are saying that the behavior, addiction, is related to an underlying phenotype, anxious-impulsive personality traits, which in turn have a genetic connection. Another common example is colonic polyps which if left alone for long periods tend to become cancerous.

This article assumes that addiction disorders depend on antecedent behavior or features or traits which may be inherited. So, substance abuse which is highly prevalent in anxiety, affective, and impulse control disorders may be a manifestation of an underlying neural dysregulation of motivation, arousal, impulsivity, reward sensitivity or impaired executive function.

In the Ersche study, 45 of the 50 stimulant dependent probands were using during the study thus avoiding any confounds arising from withdrawal. The authors were then measuring the characteristics likely to indicate genetic risk for the condition. They measured environmental, behavioral, cognitive, and social factors and focused on similar features shared by drug dependent subjects and their unaffected siblings that were not shared by healthy comparitors.

The important findings include the following. Stimulant dependence is strongly related to impulsivity and especially impaired response inhibition. The results also showed greater impulsive and anxious personality traits in probands.  They also demonstrated a strong positive correlation between impulsivity and anxiety which may be related to dysregulation of arousal. A type of impulsivity associated with negative or stressful emotion results in responses which may contribute to suicidal behavior which is a risk in substance use disorders.

The investigators also examined the impact of early environmental stressors and chaotic family life. They found that stressful events and stimulants interact to produce a reinforcing pattern leading to increased stimulant usage. This may be the mechanism that leads from sporadic usage to addictive use and further suggests that susceptibility to substance use disorder may lie in susceptibility to the behavioral sensitization.  Conversely, it suggests that siblings may be resistant if they do not have this susceptibility even though they share the same environment.

A cautionary note should be sounded, however. The subjects of this study do not possess the genome they were born with but one that has been modified epigenetically by stress and stimulant usage in the probands. The differences between the probands and their siblings could either be accounted for by inheritance or epigenetic consequences of stimulant usage. Interestingly, this study does not address the issue of resilience which was the topic of the prior blog.


Dr. Philip Grossi
Wednesday, 31 October 2012

In the last few days I have watched some of the TV coverage of hurricane Sandy and the devastation it caused.  Many public figures referred repeatedly to the resilience of the suffering citizens and that they would overcome the adversity. In the office I often ask patients to assess their progress on a scale of one to ten. Yesterday I asked such a patient and he responded that he was about at six. I asked what needed to change to get him to the nine or ten range.  He responded that he would need to feel more emotional resilience. By this he meant an increased ability to bounce back from trauma, adversity or hardship. We see this complex process played out on each fall weekend in football games we watch. Football is a game of overcoming adversity.

In humans the stress response to adversity is mediated by the sympathetic nervous system, the hypothalamic pituitary axis, neuropeptide Y, and the serotonin system. These in turn are influenced by the genes that encode variants of the components of those systems. An example I have previously blogged about (Not So Fast) is the long and short serotonin transporter resulting in differential serotonin uptake from the synapse and a differential risk of depression and response to stress. Repeated stress in childhood can result in learned helplessness and can cause exaggerated responsiveness to future stress.  On the other hand, childhood stressors that are mastered help an individual become stress-adaptive and thus more resilient than normal.

Some psychological factors related to resilience are a history of mastery of problems and challenges, i.e., a history of success; loving caretakers; robust social support; cognitive flexibility, i.e., the ability to view issues from multiple positive and negative viewpoints; physical fitness; strong commitment to developing or enhancing skills; good and constant role models; quick recovery from stressful events; careful reflection and consideration of life's experiences and drawing conclusions from them; curiosity; espousing and adhering to important values.

To summarize, resilience in humans who face stress depends on genetic, cognitive, psychological, neurobiological, developmental, and protective factors.


Dr. Philip Grossi
Monday, 15 October 2012

In the last couple of years, Zarate et. al. have done depression research with an old drug that has been used as an anesthetic. This research may be the most important development in depression therapeutics in the past fifty years. Antidepressants currently available are derived from developments in the 1950s.  At that time drugs used to treat tuberculosis were found to be monoamine oxidase inhibitors and this led to the monoamine theory of depression which was formally enunciated in the 1965 paper by Joseph Schilkraut. This led to research which eventuated in the SSRI drugs and other modern antidepressants. These drugs take weeks to produce a therapeutic response and are only moderately effective in about two thirds of patients.  In contrast, ketamine, an N-methyl-o-aspartate antagonist, produces an antidepressant effect within hour and works in individuals who are resistant to typical antidepressants.

There are accumulating studies that show that depression is associated with reduced brain size in the prefrontal cortex and hippocampus and decreased neuronal synapses in those regions.  Typical antidepressants can reverse these changes albeit slowly.  Ketamine rapidly produces synaptogenesis and reverses synaptic deficits produced by stress and depression. This in turn suggests a new theory of depression, i.e., one of synaptogenic impairment and impoverishment. It also suggests that treatment of depression should be directed to correct these connections.

Typical antidepressants increase neuroplasticity as demonstrated by Rath with their electrophysiological studies showing enhanced synaptic transmission and long term potentiation.  Other studies demonstrate antidepressant effects on BDNF, spine density, and blocking of spine atrophy by chronic stress. Yet these are slow-acting and work on modulatory neurotransmitters. A single dose of ketamine alleviates depressive symptoms within hours and the effects last about ten days. This drug increases the number and function of synaptic connections which has focused depression research on synaptogenesis as a central actor in mood control and regulation.

From a clinical standpoint, ketamine research has been done with infusions, i.e., I.V. drip done in a surgicenter.  More recently four psychiatrists at the Harvard medical school have treated bipolar II patients with IM injections. They have reported positive results in a letter to the editor in the August 2012 American Journal of Psychiatry.  It is likely that this treatment will be offered in my office in the next few months.