We have identified a subset of patients with MDD in whom sympathetic nervous activity is extraordinarily high, including in the sympathetic outflow to the heart. Treatment with an SSRI may reduce sympathetic activity in a manner likely to reduce cardiac risk.

Context:The biological basis for the development of major depressive disorder (MDD) remains incompletely understood.Objective: To quantify brain serotonin (5-hydroxytryptamine ) turnover in patients with MDD.Design: Patients with depression were studied both untreated and during administration of a selective serotonin reuptake inhibitor (SSRI) in an unblinded study of sequential design. Healthy volunteers were examined on only 1 occasion. Direct internal jugular venous blood sampling was used to directly quantify brain serotonin turnover. The effect of serotonin transporter (5-HTT) genotype on brain serotonin turnover was evaluated and the influence of SSRI therapy on serotonin turnover was investigated.Setting: Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the research catheterization laboratory of a major training hospital and medical research institute. Conclusions: Brain serotonin turnover is elevated in unmedicated patients with MDD and is influenced by the 5-HTT genotype. The marked reduction in serotonin turnover following SSRI treatment and the accompanying improvement in symptoms suggest that high brain serotonin turnover may be a biological substrate of MDD. Psychiatry. 2008;65(1):38-46 T HE ETIOLOGY OF MAJOR DEpressive disorder (MDD) has been linked to brain monoaminergic neuronal dysfunction. Arch Gen1,2 Of particular interest is the role of brain serotonin (5-hydroxytryptamine [5-HT]) in MDD. The diversity of roles played by serotonin coupled with the lack of a demonstrated relationship between different clinical presentations and biochemical abnormalities has hampered the development of sensitive markers of the disease. Indeed, brain serotonin-releasing neurons subserve diverse although incompletely understood functions related to emotions and behavior, feeding and adiposity, 3 and light stimulation. 4 We have previously demonstrated influences of obesity and feeding 5 and season and sunlight 6 on brain serotonin turnover in humans. The principal means of intraneuronal metabolism of serotonin is via oxidative deamination by monoamine oxidase resulting in formation of 5-hydroxyindoleacetic acid (5-HIAA) (Figure 1). Deamination followed by reduction, conjugation with sulfate or glucuronide, and

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.

There exists a growing body of evidence linking depression with cardiovascular events, although the mechanisms responsible remain unknown. We investigated the role of the autonomic nervous system and inflammation in the link between coronary heart disease and major depressive disorder (MDD), and examined the cardiac risk modification following pharmacological treatment of depression. We measured cardiac baroreflex function, heart rate variability, pulse pressure and high sensitivity C-reactive protein (hsCRP), all of which have an impact on cardiac risk, pre-and post-treatment in 25 patients with MDD, with no history of coronary heart disease, and in 15 healthy subjects. Treatment consisted of selective serotonin reuptake inhibitors for approximately 12 weeks. No significant differences were observed between untreated MDD patients and healthy subjects in blood pressure, heart rate, baroreflex sensitivity or heart rate variability.Pulse pressure and hsCRP, however, were significantly elevated in patients with MDD prior to treatment (p =0.023 and p =0.025, respectively). Moreover, while pharmacotherapy was effective in alleviating depression, surprisingly, each of cardiac baroreflex function, heart rate variability, pulse pressure and hsCRP was modified (p <0.05) in a manner likely to increase cardiac risk. In conclusion, this study demonstrated higher pulse pressure and hsCRP plasma levels in patients with MDD, which might contribute to increased cardiac risk. Following treatment vagal activity was reduced, as indicated by reductions in baroreflex sensitivity and heart rate variability, accompanied by increases in pulse pressure and plasma hsCRP levels. Mechanisms potentially responsible for generating cardiac risk in patients treated with selective serotonin reuptake inhibitors may need to be therapeutically targeted to reduce the incidence of coronary heart disease in this pop-

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.