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Quetiapine is an antipsychotic drug whose effect appears to be mediated through antagonist activity at the dopamine and serotonin receptors. While Quetiapine is not currently classified as a controlled substance, there have been a growing number of reports of the drug being abused both in American prisons and in general community settings. These accounts have included reports of both intranasal and intravenous uses. In this paper we report two cases of prisoners deliberately feigning psychotic symptoms for the purposes of obtaining quetiapine. In both cases there appears to be some evidence of psychological dependence and of a discontinuation syndrome when the medication was ceased. Our report adds support to the possibility that quetiapine has clinically relevant reinforcing properties with potential for producing both dependence and withdrawal symptoms and as such it should be re-evaluated as a drug with addictive potential and abuse risk.

It has always seemed plausible that short-term mental stress can act as a trigger for cardiac catastrophes, but the scientific evidence until recently was unconvincing. Panic disorder provides a special case, illustrating that mental stress responses can be a cause of triggered adverse heart events such as myocardial infarction and sudden death. In recent years systematic evidence has been gathered at times of disasters including war, missile attacks on civilians and earthquakes, which also strongly supports the proposition of an acute mental stress–heart attack link. Do these observations have a generality, applicable to the population at large? The answer is that no doubt they do, a finding reached by several national health bodies deliberating on this previously contested question. In individual personal life, ‘emotional earthquakes’ do occur. Heart attacks have been well documented to be triggered when very distressing news has been received involving family members, by armed robbery, assaults and even sporting teams or racehorses losing narrowly (or even winning) after a gripping struggle. The activation of the sympathetic nerves of the heart is of prime importance in such triggering of cardiac catastrophes by acute mental stress. It has always seemed plausible that short-term mental stress can act as a trigger for the development of abnormal heart rhythm and sudden death in patients with existing heart disease. For many years the existence of this relation of acute mental stress to heart attacks was largely based on individual anecdotes such as the celebrated case of the famous 18th-century English surgeon John Hunter, who wrote that he was at the mercy of any scoundrel who aggravated him, then subsequently proved the point by dying suddenly in the middle of a stormy meeting of the board of his hospital (Figure 1). Key to understanding the mechanisms by which triggering of heart attacks might occur is consideration of the ways in which the sympathetic nervous system and adrenal medulla are engaged in acute mental stress responses. Copyright © 2008 John Wiley & Sons, Ltd.

Integrating into the clinical practice of medicine the recent evidence that psychiatric illness and mental stress contributes to the development of cardiovascular disease has not been a seamless process. The evidence for such a link, in fact, had been slow in materializing. The importance of acute mental stress as a trigger for cardiac catastrophes (acute myocardial infarction, sudden death) and of depressive illness as a cause of coronary heart disease, however, is now firmly established. But the spectre of workplace litigation still does hang over the field, clouding the arguments and polarizing medical opinion. Now that a consensus finally seems to have been reached that mental stress, including in the workplace, is an important cause of coronary heart disease and hypertension, it is hoped that the primary outcome will be the implementation of preventive measures to reduce stress in the workplace, such as worker empowerment to end the very adverse high demand/low job control scenario, rather than a rash of lawsuits. Copyright © 2008 John Wiley & Sons, Ltd.

Patients with panic disorder are at increased cardiac risk. While the mechanisms responsible remain unknown, activation of the sympathetic nervous system may be implicated. Using isotope dilution methodology, investigations of whole-body and regional sympathetic nervous activity have failed to show any differences between patients with panic disorder and healthy subjects. Using direct recording of single unit efferent sympathetic vasoconstrictor nerve activity by microneurography we examined sympathetic nervous function in patients with panic disorder more precisely than previously reported. The activity of multiunit and single unit vasoconstrictor sympathetic nerves was recorded at rest at the level of the peroneal nerve in 10 patients diagnosed with panic disorder and in nine matched healthy volunteers. Multiunit sympathetic activity was not different between the two groups (26 ± 3 bursts min−1 in patients with panic disorder and 28 ± 3 bursts min−1 in controls). The firing frequency of single unit vasoconstrictor neurones was also similar between the two groups (0.38 ± 0.09 versus 0.22 ± 0.03 Hz). However, the probability of firing during a sympathetic burst was higher in patients with panic disorder compared with healthy controls (45 ± 5%versus 32 ± 3%, P < 0.05). When only the neural bursts during which the vasoconstrictor neurone was active were considered, we found that in patients with panic disorder the neurones tended to fire more often in a ‘multiple spike’ pattern than in the controls (i.e. the probability of the neurone firing twice was 25 ± 3% in patients with panic disorder compared with 14 ± 3% in controls). Quantification from single vasoconstrictor unit recording provides evidence of a disturbed sympathetic firing pattern in patients with panic disorder.

This study describes an internet-based intervention for people with panic disorder that consisted of a 5-module program. Participants accessed the program for 5-8 weeks and were then re-assessed 3 months later. Use of the program was associated with reductions in severity of panic disorder and in catastrophic misinterpretation of ambiguous panic body sensations in 9 people with this anxiety disorder. There were also non-significant trends for body vigilance to decrease over the course of the study. Further investigations of the efficacy of this medium for the treatment of panic disorder and the associated mechanisms of change are warranted.

Since the brain neurotransmitter changes characterising panic disorder remain uncertain, we quantified brain noradrenaline and serotonin turnover in patients with panic disorder, in the absence of a panic attack. Thirty-four untreated patients with panic disorder and 24 matched healthy volunteers were studied. A novel method utilising internal jugular venous sampling, with thermodilution measurement of jugular blood flow, was used to directly quantify brain monoamine turnover, by measuring the overflow of noradrenaline and serotonin metabolites from the brain. Radiographic depiction of brain venous sinuses allowed differential venous sampling from cortical and subcortical regions. The relation of brain serotonin turnover to serotonin transporter genotype and panic disorder severity were evaluated, and the influence of an SSRI drug, citalopram, on serotonin turnover investigated. Brain noradrenaline turnover in panic disorder patients was similar to that in healthy subjects. In contrast, brain serotonin turnover, estimated from jugular venous overflow of the metabolite, 5-hydroxyindole acetic acid, was increased approximately 4-fold in subcortical brain regions and in the cerebral cortex (P < 0.01). Serotonin turnover was highest in patients with the most severe disease, was unrelated to serotonin transporter genotype, and was reduced by citalopram (P < 0.01). Normal brain noradrenaline turnover in panic disorder patients argues against primary importance of the locus coeruleus in this condition. The marked increase in serotonin turnover, in the absence of a panic attack, possibly represents an important underlying neurotransmitter substrate for the disorder, although this point remains uncertain. Support for this interpretation comes from the direct relationship which existed between serotonin turnover and illness severity, and the finding that SSRI administration reduced serotonin turnover. Serotonin transporter genotyping suggested that increased whole brain serotonin turnover most likely derived not from impaired serotonin reuptake, but from increased firing in serotonergic midbrain raphe neurons projecting to both subcortical brain regions and the cerebral cortex.

Panic disorder can serve as a clinical model for testing whether mental stress can cause heart disease. Potential neural mechanisms of cardiac risk are the sympathetic activation during panic attacks, continuing release of adrenaline as a co-transmitter in the cardiac sympathetic nerves, and impairment of noradrenaline neuronal reuptake, augmenting sympathetic neural respnses. The phenotype of impaired neuronal reuptake of noradrenaline: an epigenetic mechanism? We suspect that this phenotype, in sensitizing people to heart symptom development, is a cause of panic disorder, and by magnifying the sympathetic neural signal in the heart, underlies increased cardiac risk. No loss of function mutations of the coding region of the norepinephrine transporter (NET) are evident, but we do detect hypermethylation of CpG islands in the NET gene promoter region. Chromatin immunoprecipitation methodology demonstrates binding of the inhibitory transcription factor, MeCP2, to promoter region DNA in panic disorder patients. Cardiovascular illnesses co-morbid with panic disorder. Panic disorder commonly coexists with essential hypertension and the postural tachycardia syndrome. In both of these cardiovascular disorders the impaired neuronal noradrenaline reuptake phenotype is also present and, as with panic disorder, is associated with NET gene promoter region DNA hypermethylation. An epigenetic ‘co-morbidity’ perhaps underlies the clinical concordance. Brain neurotransmitters. Using internal jugular venous sampling, in the absence of a panic attack we find normal norepinephrine turnover, but based on measurements of the overflow of the serotonin metabolite, 5HIAA, a marked increase (six to sevenfold) in brain serotonin turnover in patients with panic disorder. This appears to represent the underlying neurotransmitter substrate for the disorder. Whether this brain serotonergic activation is a prime mover, or consequential on other primary causes of panic disorder, including cardiac sensitization by faulty neuronal noradrenaline reuptake leading to cardiac symptoms and the enhanced vigilance which accompanies them, is unclear at present.

Background The risk of adverse clinical cardiac events is increased in patients with panic disorder (PD). We evaluated possible mechanistic links between PD and heart disease. We estimated cardiac vagal activity from heart rate variability (HRV) measurements and quantified sympathetic nervous system (SNS) activity using plasma noradrenaline tracer kinetics methodology. Methods Thirty-nine people with PD and 39 age- and gender-matched healthy volunteers were studied. In 19 participants with PD, both HRV and plasma noradrenaline kinetics were tested; in 20 with PD and 20 healthy volunteers, HRV measurements only were made, whereas in 19 healthy volunteers, noradrenaline kinetics only was tested. All panic disorder participants completed psychological measures of anxiety sensitivity and state and trait anxiety; healthy volunteers in whom HRV was measured also provided psychological measures. Results Sympathetic nervous tone in the heart, based on rates of cardiac noradrenaline spillover, was normal in PD. Noradrenaline and adrenaline plasma clearance and plasma tritiated noradrenaline and adrenaline extraction in transit through the heart, all dependent on the noradrenaline transporter (NET), were reduced in PD. Psychometric testing linked inhibition of anger to this deficit in NET functioning. Anxiety sensitivity was specifically associated with impaired cardiac NET. High- and low-frequency heart rate spectral power was unrelated to all plasma noradrenaline kinetics measurements. Conclusion Defective neuronal reuptake of noradrenaline, by augmenting the sympathetic neural signal in the heart, might have a dual effect, sensitizing the heart such as to lead to symptom development (and thus perhaps causing panic disorder) and, second, potentially contributing to adverse cardiac events in established PD.