David Baxter PhD
Late Founder
Panic Disorder Treatment: Cutting Edge Research and Its Implications
R. Bruce Lydiard, PhD, MD
Psychiatry Weekly, Volume 3, Issue 8, February 25, 2008
This interview was conducted on January 8, 2008 by Lonnie Stoltzfoos
?It is a grim irony that the more worried or anxious a person is about having a panic attack, the more likely they are to have one,? says Dr. R. Bruce Lydiard. ?There appears to be a threshold for arousal that is driven by the worry that reduces the threshold of having an attack. It is quite different, however, for people who have the attacks and don?t worry that much about them.?
Panic disorder (PD) prevalence estimates generally run at 3% of the population at any given time, and women are twice as often affected as men. According to Dr. Lydiard, ?Of those who have PD, a substantial percentage, which varies depending on the sample, have some degree of fearful avoidance?agoraphobia. Therein lies the disability associated with this disorder, and it is often a measure of the degree to which the person?s life has been disrupted.?
Agoraphobia in this context, as Dr. Lydiard explains, ?is simply when people become fearful of, or avoid, situations in which they worry that they will have an attack, or in which they have previously had attacks. Other factors include situations such as being too far away from a significant other, being far away from home, and, for some people, not knowing where their doctors are.?
The main ways panic disorder or panic disorder with agoraphobia come to the attention of the medical community, according to Dr. Lydiard, are: cardio respiratory distress, where people experience what feels like a heart attack; neurological symptoms, such as numbness, tingling, or a sense of imbalance; and gastrointestinal symptoms, such as the fear of losing control of one?s bowels.
Current Understanding and Research
There are some recent findings that, combined with older, established evidence, are introducing some interesting insights into the brain mechanisms of treating PD. ?We know that individuals who have PD have lower levels of the inhibitory transmitter, GABA,? explains Dr. Lydiard. ?Previous research has measured the response to intravenous diazepam in drug na?ve PD patients versus normal comparison subjects. As they logarithmically increased the dosage, several things happened: nearly all the controls fell asleep before reaching the highest dose, while only one PD patient fell asleep. The endpoint they were looking for, however, was nystagmus?rapid eye movements. It took significantly higher doses to elicit nystagmus in PD patients than in controls. This suggests that the receptors of PD patients are less sensitive to the benzodiazepines. Doctors often worry about prescribing high doses of benzodiazepines, but, in terms of the clinical realm, these patients might not be drug-seeking; they might be trying to gain a normal state.?
While this finding has not been specifically correlated with newer studies, it is consistent with abnormalities in the GABAergic system in panic disorder. A 2007 finding by Cameron and colleagues also reported a decreased receptor binding in the insular cortex bilaterally; individuals with PD and comorbid depression had the lowest binding.
Many clinicians and patients worry about ?addiction? to benzodiazepines. ?There is, however, no evidence that there is a significant abuse problem with benzodiazepines for people in treatment for an anxiety or panic disorder,? remarks Dr. Lydiard. ?In fact, dosages required by PD patients appear to decrease over time. One would think the opposite would be true?that patients were either abusing or becoming tolerant to the anxiolytic effects of benzodiazepines?but to the present day there is no evidence of a rapidly escalating dose in people who have been treated for many years with benzodiazepines.?
Another broad approach that has gained traction over the past several years is the idea of viewing PD from a psychosomatic approach?the medical understanding that places no distinct boundaries between the body and the mind. A 2003 study by Hudson and colleagues evaluated the familial aspect of affective spectrum disorder, which represents a number of medical and psychiatric conditions all known to respond to antidepressants, including fibromyalgia, irritable bowel syndrome, migraine, GAD, depression, PD and others. ?All of these so-called somatic disorders have stress reactivity characteristics,? says Dr. Lydiard. ?Findings from studies of the various abnormalities of the hypothalamic pituitary adrenal (HPA) stress systems have been shown to vary between these conditions, but what they do have in common is some degree of HPA dysregulation. For example, if one has too much cortisol over an extended period of time, the glucocorticoid receptors become less responsive to it. Or, if you don?t have enough, such as a PTSD patient, one may be unable to muster enough cortisol to shut off the stress response. So these disorders do have some common neurobiologic underpinnings.?
The inability to regulate the stress response system is important, according to Dr. Lydiard, who believes this is common in anxiety and depression.
?The way we define depression is a perceived threat, and a perceived inability to control that threat or challenge,? he says, ?and that is exactly what PD is. It?s unpredictable, and it?s impossible to control it for the individual.? Although he says it has not been proven, Dr. Lydiard says it is reasonable to speculate that there is shared pathophysiology for a variety of problems mediated in part by increased pro-inflammatory cytokine activity, including cardiovascular problems, hypertension, asthma, or migraines?all of which have a fairly consistent association with PD. Chronic stress causes alterations in the immune system, which is caused by persistent activation of the hypothalamic pituitary adrenal axis. ?Although this hypothesis makes sense,? says Dr. Lydiard, ?it has not been rigorously studied. And while it would be difficult to do so, future research will surely address this hypothesis.?
Treatment Refractory Panic Disorder
In a 2007 review on treating drug-refractory PD, Dr. Lydiard emphasizes that none of the pharmacologic agents effective for PD have an established, superior efficacy. Combined cognitive behavior therapy (CBT) and medication is a viable option for refractory PD. Four different classes of drugs have demonstrated similar efficacy for treating PD: SSRIs, SNRIs, TCAs, and benzodiazepines. SSRIs and SNRIs are the recommended first-line treatment. Patients with PD may require higher doses of antidepressants or benzodiazepines, which are twice as high as for other disorders. For patients with mild or moderate symptoms of PD, CBT alone may be effective without medication. Dr. Lydiard says the clinicians experience with CBT is very important, and the limited data suggest that a minimum of 12 CBT sessions with an experienced clinician is recommended.
?According to the evidence, no combination treatment, such as CBT and medication, has shown substantially superior efficacy over a solitary treatment for PD, whether CBT alone or medication alone,? says Dr. Lydiard. ?In either case, patients should be kept informed each step of the way when forming a treatment strategy, whatever pharmacologic agents that may entail. Our main approach has been to work with agents that are approved and to optimize treatment for that. TCAs such as imipramine have not been approved, but are also clearly effective; side effects diminish enthusiasm for their use, which is why SSRIs and SNRIs are preferred.?
R. Bruce Lydiard, PhD, MD
Psychiatry Weekly, Volume 3, Issue 8, February 25, 2008
This interview was conducted on January 8, 2008 by Lonnie Stoltzfoos
?It is a grim irony that the more worried or anxious a person is about having a panic attack, the more likely they are to have one,? says Dr. R. Bruce Lydiard. ?There appears to be a threshold for arousal that is driven by the worry that reduces the threshold of having an attack. It is quite different, however, for people who have the attacks and don?t worry that much about them.?
Panic disorder (PD) prevalence estimates generally run at 3% of the population at any given time, and women are twice as often affected as men. According to Dr. Lydiard, ?Of those who have PD, a substantial percentage, which varies depending on the sample, have some degree of fearful avoidance?agoraphobia. Therein lies the disability associated with this disorder, and it is often a measure of the degree to which the person?s life has been disrupted.?
Agoraphobia in this context, as Dr. Lydiard explains, ?is simply when people become fearful of, or avoid, situations in which they worry that they will have an attack, or in which they have previously had attacks. Other factors include situations such as being too far away from a significant other, being far away from home, and, for some people, not knowing where their doctors are.?
The main ways panic disorder or panic disorder with agoraphobia come to the attention of the medical community, according to Dr. Lydiard, are: cardio respiratory distress, where people experience what feels like a heart attack; neurological symptoms, such as numbness, tingling, or a sense of imbalance; and gastrointestinal symptoms, such as the fear of losing control of one?s bowels.
Current Understanding and Research
There are some recent findings that, combined with older, established evidence, are introducing some interesting insights into the brain mechanisms of treating PD. ?We know that individuals who have PD have lower levels of the inhibitory transmitter, GABA,? explains Dr. Lydiard. ?Previous research has measured the response to intravenous diazepam in drug na?ve PD patients versus normal comparison subjects. As they logarithmically increased the dosage, several things happened: nearly all the controls fell asleep before reaching the highest dose, while only one PD patient fell asleep. The endpoint they were looking for, however, was nystagmus?rapid eye movements. It took significantly higher doses to elicit nystagmus in PD patients than in controls. This suggests that the receptors of PD patients are less sensitive to the benzodiazepines. Doctors often worry about prescribing high doses of benzodiazepines, but, in terms of the clinical realm, these patients might not be drug-seeking; they might be trying to gain a normal state.?
While this finding has not been specifically correlated with newer studies, it is consistent with abnormalities in the GABAergic system in panic disorder. A 2007 finding by Cameron and colleagues also reported a decreased receptor binding in the insular cortex bilaterally; individuals with PD and comorbid depression had the lowest binding.
Many clinicians and patients worry about ?addiction? to benzodiazepines. ?There is, however, no evidence that there is a significant abuse problem with benzodiazepines for people in treatment for an anxiety or panic disorder,? remarks Dr. Lydiard. ?In fact, dosages required by PD patients appear to decrease over time. One would think the opposite would be true?that patients were either abusing or becoming tolerant to the anxiolytic effects of benzodiazepines?but to the present day there is no evidence of a rapidly escalating dose in people who have been treated for many years with benzodiazepines.?
Another broad approach that has gained traction over the past several years is the idea of viewing PD from a psychosomatic approach?the medical understanding that places no distinct boundaries between the body and the mind. A 2003 study by Hudson and colleagues evaluated the familial aspect of affective spectrum disorder, which represents a number of medical and psychiatric conditions all known to respond to antidepressants, including fibromyalgia, irritable bowel syndrome, migraine, GAD, depression, PD and others. ?All of these so-called somatic disorders have stress reactivity characteristics,? says Dr. Lydiard. ?Findings from studies of the various abnormalities of the hypothalamic pituitary adrenal (HPA) stress systems have been shown to vary between these conditions, but what they do have in common is some degree of HPA dysregulation. For example, if one has too much cortisol over an extended period of time, the glucocorticoid receptors become less responsive to it. Or, if you don?t have enough, such as a PTSD patient, one may be unable to muster enough cortisol to shut off the stress response. So these disorders do have some common neurobiologic underpinnings.?
The inability to regulate the stress response system is important, according to Dr. Lydiard, who believes this is common in anxiety and depression.
?The way we define depression is a perceived threat, and a perceived inability to control that threat or challenge,? he says, ?and that is exactly what PD is. It?s unpredictable, and it?s impossible to control it for the individual.? Although he says it has not been proven, Dr. Lydiard says it is reasonable to speculate that there is shared pathophysiology for a variety of problems mediated in part by increased pro-inflammatory cytokine activity, including cardiovascular problems, hypertension, asthma, or migraines?all of which have a fairly consistent association with PD. Chronic stress causes alterations in the immune system, which is caused by persistent activation of the hypothalamic pituitary adrenal axis. ?Although this hypothesis makes sense,? says Dr. Lydiard, ?it has not been rigorously studied. And while it would be difficult to do so, future research will surely address this hypothesis.?
Treatment Refractory Panic Disorder
In a 2007 review on treating drug-refractory PD, Dr. Lydiard emphasizes that none of the pharmacologic agents effective for PD have an established, superior efficacy. Combined cognitive behavior therapy (CBT) and medication is a viable option for refractory PD. Four different classes of drugs have demonstrated similar efficacy for treating PD: SSRIs, SNRIs, TCAs, and benzodiazepines. SSRIs and SNRIs are the recommended first-line treatment. Patients with PD may require higher doses of antidepressants or benzodiazepines, which are twice as high as for other disorders. For patients with mild or moderate symptoms of PD, CBT alone may be effective without medication. Dr. Lydiard says the clinicians experience with CBT is very important, and the limited data suggest that a minimum of 12 CBT sessions with an experienced clinician is recommended.
?According to the evidence, no combination treatment, such as CBT and medication, has shown substantially superior efficacy over a solitary treatment for PD, whether CBT alone or medication alone,? says Dr. Lydiard. ?In either case, patients should be kept informed each step of the way when forming a treatment strategy, whatever pharmacologic agents that may entail. Our main approach has been to work with agents that are approved and to optimize treatment for that. TCAs such as imipramine have not been approved, but are also clearly effective; side effects diminish enthusiasm for their use, which is why SSRIs and SNRIs are preferred.?
