Basilar artery blood flow velocity changes in patients with panic disorder following 35% carbon dioxide challenge
Alkin T, Tural U, Onur E, Ozturk V, Monkul ES, Kutluk K;
Commented by , 30 Mar 2007
Aim of the study
To assess the effect of 35% CO2 inhalation on basilar artery blood flow velocity (BABFV) in patients with panic disorder before and after paroxetine treatment.
Method
Right handed patients with panic disorder with or without agoraphobia (n=24) were included in the study. Panic disorder was diagnosed with the Structured Clinical Interview for DSM-IV Axis I Disorders, and all patients were either drug naïve or had stopped taking their medication at least 15 days prior to the study.
Patients were excluded if they had a concurrent axis I disorder diagnosis, a history of bipolar disorder or schizophrenia, a substance abuse diagnosis six months prior to testing or history of substance dependency (excluding nicotine). Patients were also free of head trauma with loss of consciousness, neurological disease and mental retardation.
Twelve age and gender matched controls that did not have a current or past diagnosis of panic disorder, major mood disorder, substance use disorder or schizophrenia, were included for comparison.
BABFV was measured using transcranial Doppler ultrasound, prior to, and at several time points following, inhalation of the 35% CO2 gas mixture. Panic attack symptoms were assessed using Visual Analogue Scales (VAS). A panic attack was defined as an increase of more than 25% in at least four VAS symptoms.
Results
Patients and controls did not differ on BABFV at rest (p=0.528). 10 patients and 2 controls panicked following CO2 inhalation. CO2 inhalation increased mean BABFV in patients (p<0.001) but not controls (p=0.498). Paroxetine treatment reduced the mean BABFV following CO2 inhalation compared to pre-treatment levels (p=0.019), but the time course of this effect was the same before and after treatment.
Furthermore, BABFV increase following CO2 inhalation was greater in those patients that panicked compared to those that did not (p=0.038). No significant difference between those that did and did not respond to treatment was seen in the mean BABFV.
Dr Hood's and Prof Nutt's comments
There have been a number of reports of dysfunctional cerebral blood flow in patients with panic disorder. This study adds to the evidence base by demonstrating 35% CO2 induced differential change in blood flow velocity between panic disorder and controls in the basilar artery.
This artery supplies the locus ceruleus, and brainstem autonomic and respiratory centres - brain regions implicated in panic disorder (ref. 1). Although a greater increase in blood flow velocity was seen in patients who panicked following CO2 inhalation, whether this difference reflects an anxiety state, respiratory dysfunction or haemodynamic dysfunction is not clear.
The mechanism of CO2 induced panic remains unknown, despite numerous studies investigating this panicogen. It is clear that CO2 activates the HPA axis, however as this happens to a similar degree in control participants and panic disorder patients (ref. 2) it is unlikely that activation of this axis that is primarily involved in the generation of panic attacks.
Furthermore, although CO2-induced panic supports Klein's false suffocation-alarm theory of panic (ref. 3) controversy still exists, not in the least whether dyspnea is a defining feature of panic disorder (ref. 4).
Chemosensitive (CO2-sensitive) serotonergic neurones in the rostral ventral medulla may provide an alternative connection between hyperventilation-induced respiratory alkalosis and sympathetic activation (ref. 5); in turn serotonergic modulation of the sympathetic nervous system via ventrolateral periaqueductal gray is described (ref. 6).
Thus, there are preclinical data linking panic, serotonin and the autonomic nervous system which our group is also investigating (ref. 7, ref. 8). This association should not be all that surprising – after all, the term "serotonin" itself was coined upon the discovery of a substance that was found in "serum" that increased vascular "tone".
Psychiatrists traditionally have relied upon psychological measures as clinical experimental outcomes. In contrast, Esler's group – approaching this from a cardiologist's perspective – reported excess adrenergic output from the heart and kidneys in panic disorder at rest and from multiple organs during panic attacks using coronary sinus catheterisation with radiolabeled catecholamines amongst other techniques (ref. 9). They cite 10 studies in which less invasive venous sampling had given inconsistent results.
The apparent reticence of psychology/psychiatry investigators to conduct similarly invasive studies speaks to the gap between clinical and preclinical research in this area. Studies such as Alkin et al. reported above may represent a "third way" to approach this - developing and refining "hard" non-invasive biological measures of anxiety disorders and by demonstrating a willingness to work across traditional disciplinary boundaries, especially with our cardiovascular colleagues.
Novel methodologies such as circadian heart rate psychiatric diagnosis are in their infancy but promise much (ref. 10), yet the inertia of the psychiatric establishment hinders its refinement.
Unless we start to gird ourselves against our reluctance to conduct the sorts of "hard" biological studies that our medical peers engage in, then it seems likely that the biological correlates of mental disorders will continue to remain elusive.
References
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