Quantification of cerebral blood flow as biomarker of drug effect: arterial spin labeling phMRI after a single dose of oral citalopram.

Arterial spin labeling (ASL) allows noninvasive quantification of cerebral blood flow (CBF), which can be used as a biomarker of drug effects in pharmacological magnetic resonance imaging (phMRI). In a double-blind, placebo-controlled crossover study, we investigated the effects of a single oral dose of citalopram (20 mg) on resting CBF in 12 healthy subjects, using ASL phMRI. Support-vector machine (SVM) analysis detected significant drug-induced reduction in CBF in brain regions including the amygdala, fusiform gyrus, insula, and orbitofrontal cortex. These regions have been shown to have abnormally elevated CBF in patients with major depression, as well as in subjects genetically prone to depression. Mixed-effects analysis on data extracted from selected regions of interest (ROIs) revealed significant drug effect only in serotonergic areas of the brain (z = -4.45, P < 0.005). These results demonstrate the utility of ASL phMRI as a biomarker of pharmacological activity of orally administered drugs in the brain.

A biobehavioural model of the night eating syndrome.

This paper will propose a biobehavioral mechanism for the Night Eating Syndrome (NES), a disorder characterized by a delayed circadian rhythm of food intake and neuroendocrine function. Food intake consists of at least 25% of daily caloric intake after the evening meal and/or at least two nighttime awakenings with ingestions per week. This will be explored by reviewing neuroimaging of brain serotonin transporters (SERT) and treatment with selective serotonin reuptake inhibitors (SSRIs). SERT binding is elevated in the midbrain of night eaters, causing dysregulation of the circadian rhythm of both food intake and neuroendocrine function. The administration of SSRIs blocks the reuptake of serotonin and restores the circadian rhythm of both food intake and neuroendocrine function. This hypothesis implies that reduction of SERT activity should increase postsynaptic serotonin transmission and relieve NES. This is precisely the effect of SSRIs. NES is a function of elevated SERT, and blocking of SERT with an SSRI resolves NES. This model of NES attests to the validity of the diagnosis of NES and the criteria by which it is identified, and it provides an explanation of the mechanism.

Acute mood and thyroid stimulating hormone effects of transcranial magnetic stimulation in major depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has recently been demonstrated to have antidepressant effects. Some work suggests that rTMS over prefrontal cortex administered to healthy individuals produces acute elevations of mood and serum thyroid-stimulating hormone (TSH). We sought to determine whether single rTMS sessions would produce acute mood and serum TSH elevations in subjects with major depressions. METHODS: Under double-blind conditions et al 14 medication-free subjects with major depression received individual sessions of either active or sham rTMS. rTMS was administered over the left prefrontal cortex at 10 Hz et al 100% of motor threshold, 20 trains over 10 min. Immediately before and after rTMS sessions, subjects' mood was rated with the Profile of Mood States (POMS) and the 6-Item Hamilton Depression Scale, and blood was drawn for later analysis of TSH. Subjects and raters were blind to treatment assignment. RESULTS: The group receiving active stimulation manifested significantly greater improvement on the POMS subscale of Depression (p < or = .0055) and a trend toward greater improvement on the modified Hamilton Rating (.05 < p < or =.1). No hypomania was induced. The change in TSH from pre- to post-rTMS was significantly different between active and sham sessions. CONCLUSIONS: This blinded, placebo-controlled trial documents that individual rTMS sessions can acutely elevate mood and stimulate TSH release in patients experiencing major depressive episodes.

Physiological effects of electroconvulsive therapy and transcranial magnetic stimulation in major depression.

Major depressive episodes are associated with dysregulation of various physiologic systems. Antidepressant medications alter regulation of the hormonal and sleep systems. A thorough understanding of these changes may elucidate the pathophysiologic basis of the disorder [Amsterdam et al., 1989: Psychoneuroendocrinology 14:43-62], and interventions targeted directly at these systems are being increasingly recognized as possible treatments for depression [Wong et al., 2000: Proc Natl Acad Sci USA 97:325-330; Szuba et al., 1996: Proc Am Coll Neuropsychopharmacol Ann Meet]. These physiologic systems are regulated by the major neurotransmitters implicated in the etiology of mood disorders--norepinephrine, serotonin, and dopamine. Many of the hormones of import for this article also act as neurotransmitters and thus alter cerebral activity themselves [Owens and Nemeroff, 1993: Ciba Found Symp 172:296-308; Weitzner, 1998: Psychother Psychosom 67:125-132]. Parenteral infusion of hydrocortisone [DeBattista, 2000: Am J Psychiatry 157:1334-1337] and thyrotropin-releasing hormone (TRH) [Prange et al., 1972: Lancet 2:999-1002; Marangell et al., 1997: Arch Gen Psychiatry 54:214-222; Szuba, 1996: Proc Am Coll Neuropsychopharmacol Ann Meet.] produce acute antidepressant effects. Antagonists to corticotropin-releasing hormone and repeated parenteral infusion of TRH may have antidepressant activity when given during several weeks [Wong, 2000: Proc Natl Acad Sci USA 97:325-330; Arborelius et al., 1999: J Endocrinol 160:1-12; Callahan et al., 1997: Biol Psychiatry 41:264-272]. Manipulations of the sleep system through sleep deprivation can ameliorate depression [Szuba et al., 1994: Psychiatry Res 51:283-295; see Wirz-Justice et al., 1999: Biol Psychiatry 46:445-453 for review]. Sleep deprivation has been shown in more than three dozen studies published in the last three decades to produce marked, acute antidepressant effects in the majority of depressed individuals [Wirz-Justice, et al., 1999: Biol Psychiatry 46:445-453]. Thus, examination of the effects the two nonpharmacologic treatments, electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS), produce in these physiologic systems may help elucidate their mechanisms of action, while enhancing understanding of the neurobiology of depressive illness. We will review these physiologic changes associated with depression, the effects that manipulations of these systems can have on depressive disorders, and then describe the effects the two techniques that can stimulate the human brain in vivo, ECT and TMS, exert on these systems.

Depression in the medical setting: biopsychological interactions and treatment considerations.

This article examines depression in 6 medical conditions: coronary artery disease (CAD), cancer, human immunodeficiency virus (HIV) infection, Parkinson's disease, pain, and the sex hormone changes of aging. Research is beginning to define specific biological and psychological mechanisms underlying the adverse interactions between depression and these medical conditions. Antidepressant medications, psychosocial therapies, and hormonal manipulations are effective in reducing depressive symptoms. Specific psychosocial interventions may increase longevity in CAD and cancer and may enhance quality of life in HIV infection. Newer antidepressants appear to be safer and better tolerated than older agents for medically ill patients, but do not appear to be as effective for neuropathic pain. Dopamine agonists may benefit depression associated with Parkinson's disease. Hormone replacement therapy may improve subsyndromal depressive symptoms in postmenopausal women and may enhance antidepressant response for older women with major depression.