Our goal was to determine whether treatment of depressive symptoms with escitalopram during buprenorphine treatment for opioid dependence, would improve treatment retention compared to placebo in a 12-week, randomized, double-blind trial. Treatment drop-out was defined as missing seven consecutive buprenorphine dosing days. Participants were 76% male, 80% non-Hispanic Caucasian, and 64% heroin users. At baseline, the mean Beck Depression Inventory-II (BDI-II) score was 28.4 (±9.7). Sixty-one percent of participants completed the 12 week buprenorphine protocol. Dropout rates were 33.3% and 44.0% among those randomized to escitalopram or placebo respectively (p=.19). Relative to baseline, mean BDI-II scores were significantly lower at all follow-up assessments, but the treatment by time interaction effect was not statistically significant (p = .18). Participants randomized to escitalopram also did not have a significantly lower likelihood of testing positive for either opiates or other drugs during follow-up. Depressive symptoms often resolved with buprenorphine treatment and the immediate initiation of escitalopram does not improve treatment retention, depression outcomes, or illicit drug use. Clinicians should determine the need for antidepressant treatment later in buprenorphine care.

Orthostatic intolerance (OI) or postural tachycardia syndrome (POTS) is a syndrome primarily affecting young females, and is characterized by lightheadedness, palpitations, fatigue, altered mentation, and syncope primarily occurring with upright posture and being relieved by lying down. There is typically tachycardia and raised plasma norepinephrine levels on upright posture, but little or no orthostatic hypotension. The pathophysiology of OI is believed to be very heterogeneous. Most studies of the syndrome have focused on abnormalities in norepinephrine release. Here the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to the pathophysiology in some patients with OI was tested. In a proband with significant orthostatic symptoms and tachycardia, disproportionately elevated plasma norepinephrine with standing, impaired systemic, and local clearance of infused tritiated norepinephrine, impaired tyramine responsiveness, and a dissociataion between stimulated plasma norepinephrine and DHPG elevation were found. Studies of NET gene structure in the proband revealed a coding mutation that converts a highly conserved transmembrane domain Ala residue to Pro. Analysis of the protein produced by the mutant cDNA in transfected cells demonstrated greater than 98% reduction in activity relative to normal. NE, DHPG/NE, and heart rate correlated with the mutant allele in this family. Conclusion: These results represent the first identification of a specific genetic defect in OI and the first disease linked to a coding alteration in a Na+/Cl−‐dependent neurotransmitter transporter. Identification of this mechanism may facilitate our understanding of genetic causes of OI and lead to the development of more effective therapeutic modalities.

The norepinephrine transporter (NET) has a major role in terminating the neurochemical signal established by the neurotransmitter norepinephrine (NE) in the synaptic cleft. The NET is also the initial site of action for therapeutic antidepressants, and drugs such as cocaine and amphetamines. Polymorphisms in the NET gene have been identified, and associations with several disorders such as depression have been proposed but not established. However, evidence of a direct association between a genetic mutation of the NET and an autonomic clinical syndrome has recently emerged. A patient and her identical twin were evaluated for typical symptoms of orthostatic intolerance (OI), a disorder mainly characterised by elevated heart rate on standing, and both were found to have clinical and laboratory signs of abnormal uptake of NE. Sequence analysis of the patients' NET gene identified a mutation that resulted in more than 98% loss of function as compared with the wild-type gene. This article reconsiders the important role of the NET protein in the regulation of the nervous and cardiovascular systems, reviews the literature for its polymorphisms and their suggested clinical manifestations, and finally focuses on the effects of its defect on the pathophysiology of OI, the only confirmed direct association between a genetic mutation of the NET and a clinical syndrome. Genetic or acquired deficits inthe norepinephrine transporter: current understanding of clinical implications 2 expert reviews in molecular medicine References 1 Young, J.B. and Landsberg, L. (1998) Catecholamines and the adrenal medulla. In Accession information: (01)00387-8a.pdf (short code: txt001drn); Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications 8 expert reviews in molecular medicine Accession information: (01)00387-8a.pdf (short code: txt001drn);

The purpose of this study was to determine whether schizophrenia was associated with alterations in alcohol response that might explain the elevated risk for AUDs in this population. In a randomized, double-blind, placebo-controlled, counter-balanced 3 test day laboratory study, the effects of alcohol were compared in 23 subjects with schizophrenia (without any previous alcohol use disorder (AUD) but with some alcohol exposure) and in 14 healthy subjects matched for age, gender, education, and lifetime exposure to alcohol. Standard alcohol drinks in a scheduled design were administered to produce blood alcohol levels of 0, 0.02-0.04 mg%, or 0.06-0.08 mg%. Schizophrenia symptoms, perceptual alterations, stimulant and depressant subjective effects of alcohol, and 'high' were measured before alcohol administration and at several post-drug time points. Verbal learning and recall, vigilance and distractibility, and motor function were assessed once per test day. Relative to healthy subjects, subjects with schizophrenia reported greater euphoria and stimulatory effects in response to alcohol. Alcohol produced small transient increases in positive psychotic symptoms and perceptual alterations without affecting negative symptoms. Alcohol also impaired several aspects of immediate and delayed recall, and vigilance, and distractibility. Schizophrenia patients showed increased euphoric and stimulatory responses to alcohol. These exaggerated positive responses to alcohol doses may contribute to the increased risk for AUDs associated with schizophrenia. The absence of 'beneficial' effects of alcohol does not support a self-medication hypothesis of alcohol use in schizophrenia.

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Both GABAergic and cholinergic systems are involved in central cardiovascular regulation. Previous studies have shown that GABAA receptor antagonists cause increases in blood pressure, heart rate and locomotor activity. In this study, we examined the role of the depletion of brain acetylcholine on the cardiovascular responses and locomotor activity induced by bicuculline methiodide in conscious Sprague-Dawley rats. The doses of 0.3 and 0.5 nmol of intracerebroventricular bicuculline methiodide produced increases in blood pressure, heart rate and locomotor activity. The dose of 18 nmol of hemicholinium-3 to deplete brain acetylcholine was given intracerebroventricularly one hour prior to bicuculline methiodide. The pressor responses to bicuculline methiodide in animals pretreated with the hemicholinium-3 were higher than those seen in saline-pretreated groups, but locomotor activity and heart rate responses to bicuculline methiodide remained unchanged in hemicholinium-3 pretreatment group. On the other hand, high dose of bicuculline methiodide (0.5 nmol) caused convulsions in some animals pretreated with hemicholinium-3 whereas bicuculline methiodide, alone, did not cause any seizure activity. In conclusion, it seems likely that endogenous brain acetylcholine could be a modulator of GABAA receptor-mediated blood pressure control.

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