Evaluation of Novel B1R/B2R Agonists Containing TRIOZAN™ Nanoparticles for Targeted Brain Delivery of Antibodies in a Mouse Model of Alzheimer Disease.

The blood-brain barrier (BBB) is a major obstacle to the development of effective therapeutics for central nervous system (CNS) disorders, including Alzheimer's disease (AD). This has been particularly true in the case of monoclonal antibody (mAbs) therapeutic candidates, due to their large size. To tackle this issue, we developed new nanoformulations, comprising bio-based Triozan polymers along with kinin B1 and B2 receptor (B1R and B2R) peptide agonist analogues, as potent BBB-permeabilizers to enhance brain delivery of a new anti-C1q mAb for AD (ANX005). The prepared B1R/B2R-TRIOZAN™ nanoparticles (NPs) displayed aqueous solubility, B1R/B2R binding capacity and uniform sizes (~130-165 nm). The relative biodistribution profiles of the mAb loaded into these NPs versus the naked mAb were assessed in vivo through two routes of administrations (intravenous (IV), intranasal (IN)) in the Tg-SwDI mouse model of AD. At 24 h post-administration, brain levels of the encapsulated mAb were significantly increased (up to 12-fold (IV) and 5-fold (IN), respectively) compared with free mAb in AD brain affected regions, entorhinal cortex and hippocampus of aged mice. Liver uptakes remained relatively low with similar values for the nanoformulations and free mAb. Our findings demonstrate the potential of B1R/B2R-TRIOZAN™ NPs for the targeted delivery of new CNS drugs, which could maximize their therapeutic effectiveness.

Differential Potency of Venlafaxine, Paroxetine, and Atomoxetine to Inhibit Serotonin and Norepinephrine Reuptake in Patients With Major Depressive Disorder.

BACKGROUND: Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT). METHODS: This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine. RESULTS: All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout. CONCLUSION: These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.

Long-term laryngotracheal complications following cardiac surgery.

BACKGROUND AND AIM OF THE STUDY: Long-term laryngotracheal complications have not been described in adult patients undergoing cardiac surgery. The purpose of this study was to determine the incidence of and risk factors for laryngotracheal complications following cardiac surgery. METHODS: A retrospective chart review of patients at high risk for laryngotracheal complications following cardiac surgery between 2006 and 2016 was performed. High-risk patients were reviewed to determine the presence of laryngotracheal complications including laryngotracheal stenosis, keyhole deformity, or vocal cord immobility. Logistic regression was used to identify predictors of long-term laryngotracheal complications. RESULTS: Of 11,417 patients who underwent cardiac surgery, 1099 were identified as at high risk. Of these, 24 (2.2%) developed laryngotracheal complications following their surgery and intensive care unit (ICU) stay. Laryngotracheal stenosis and keyhole deformity were present in 13 (1.2%) and 6 (0.5%) patients, respectively. Logistic regression demonstrated older age (age ≥ 70 odds ratio [OR] 0.31, 95% confidence interval [CI] 0.12-0.83) was protective, while readmission to ICU for ventilation (OR 3.11, 95% CI 1.17-8.25) and receiving a tracheostomy (OR 7.83, 95% CI 2.22-27.6) were associated with laryngotracheal complications. CONCLUSIONS: The incidence of long-term laryngotracheal complications following cardiac surgery was 2.2%. Readmission to ICU for ventilation and having a tracheostomy performed were associated with laryngotracheal complications.

Autumn larval cold tolerance does not predict the northern range limit of a widespread butterfly species.

Climate change is driving range shifts, and a lack of cold tolerance is hypothesized to constrain insect range expansion at poleward latitudes. However, few, if any, studies have tested this hypothesis during autumn when organisms are subjected to sporadic low-temperature exposure but may not have become cold-tolerant yet. In this study, we integrated organismal thermal tolerance measures into species distribution models for larvae of the Giant Swallowtail butterfly, Papilio cresphontes (Lepidoptera: Papilionidae), living at the northern edge of its actively expanding range. Cold hardiness of field-collected larvae was determined using three common metrics of cold-induced physiological thresholds: the supercooling point, critical thermal minimum, and survival following cold exposure. P. cresphontes larvae were determined to be tolerant of chilling but generally die at temperatures below their SCP, suggesting they are chill-tolerant or modestly freeze-avoidant. Using this information, we examined the importance of low temperatures at a broad scale, by comparing species distribution models of P. cresphontes based only on environmental data derived from other sources to models that also included the cold tolerance parameters generated experimentally. Our modeling revealed that growing degree-days and precipitation best predicted the distribution of P. cresphontes, while the cold tolerance variables did not explain much variation in habitat suitability. As such, the modeling results were consistent with our experimental results: Low temperatures in autumn are unlikely to limit the distribution of P. cresphontes. Understanding the factors that limit species distributions is key to predicting how climate change will drive species range shifts.

Prediction of temporary epicardial pacing wire use in cardiac surgery.

BACKGROUND: Placement of temporary epicardial pacing wires (TEPW) at the end of open heart surgery cases is routine but can be associated with complications. Identification of patients who are high risk for requiring pacing would be beneficial on guiding selective TEPW placement. The purpose of this study was to identify predictors of temporary pacing immediately post cardiac surgery. METHODS: A retrospective analysis of patients undergoing cardiac surgery from 2005 to 2016 at the Maritime Heart Center was conducted. Analysis was performed of patients who require pacing on arrival to the cardiovascular intensive care unit (CVICU) compared with those who were not paced. Multivariable logistic regression was used to determine each variable's risk adjusted likelihood of pacing for the entire cohort. Subgroup analysis was performed in the isolated procedures. RESULTS: A total of 11 752 patient underwent surgery from the year 2005 to 2016. Two thousand and fifty-one (17.5%) required pacing on arrival to CVICU. Older age, female sex, preoperative renal failure, lower ejection fraction (EF), preoperative arrhythmia, preoperative use of calcium channel blockers, and longer cross-clamp times were risk factors for pacing. In the isolated coronary artery bypass grafting and aortic valve replacement groups, findings were similar to the overall cohort. Only age, obesity, and chronic obstructive pulmonary disease were risk factors for pacing in the isolated mitral valve (MV) repair group and only preoperative arrhythmia in the isolated MV replacement group. CONCLUSION: We have identified risk factors for TEPW use following cardiac surgery and in isolated procedure subgroups. These risk factors may help guide selective TEPW placement.

Variability in opioid prescribing practices among cardiac surgeons and trainees.

BACKGROUND AND AIM: The opioid epidemic has become a major public health crisis in recent years. Discharge opioid prescription following cardiac surgery has been associated with opioid use disorder; however, ideal practices remain unclear. Our aim was to examine current practices in discharge opioid prescription among cardiac surgeons and trainees. METHODS: A survey instrument with open- and closed-ended questions, developed through a 3-round Delphi method, was circulated to cardiac surgeons and trainees via the Canadian Society of Cardiac Surgeons. Survey questions focused on routine prescription practices including type, dosage and duration. Respondents were also asked about their perceptions of current education and guidelines surrounding opioid medication. RESULTS: Eighty-one percent of respondents reported prescribing opioids at discharge following routine sternotomy-based procedures, however, there remained significant variability in the type and dose of medication prescribed. The median (interquartile range) number of pills prescribed was 30 (20-30) with a median total dose of 135 (113-200) Morphine Milligram Equivalents. Informal teaching was the most commonly reported primary influence on prescribing habits and a lack of formal education regarding opioid prescription was associated with a higher number of pills prescribed. A majority of respondents (91%) felt that there would be value in establishing practice guidelines for opioid prescription following cardiac surgery. CONCLUSIONS: Significant variability exists with respect to routine opioid prescription at discharge following cardiac surgery. Education has come predominantly from informal sources and there is a desire for guidelines. Standardization in this area may have a role in combatting the opioid epidemic.

Ramping Up the Delivery of Cardiac Surgery During the COVID-19 Pandemic: A Guidance Statement From the Canadian Society of Cardiac Surgeons.

The coronavirus disease 2019 (COVID-19) has had a profound global effect. Its rapid transmissibility has forced whole countries to adopt strict measures to contain its spread. As part of necessary pandemic planning, most Canadian cardiac surgical programs have prioritized and delayed elective procedures in an effort to reduce the burden on the health care system and to mobilize resources in the event of a pandemic surge. While the number of COVID-19 cases continue to increase worldwide, new cases have begun to decline in many jurisdictions. This "flattening of the curve" has inevitably prompted discussions around reopening of the economy, relaxing some public health restrictions, and resuming nonurgent health care delivery. This document provides a template for cardiac surgical programs to begin to ramp-up the delivery of cardiac surgery in a deliberate and graded fashion as the COVID-19 pandemic burden begins to ease that is guided by 3 principles. First, all recommendations from public health authorities regarding COVID-19 containment must continue to be followed to minimize disease spread, ensure patient safety, and protect health care personnel. Second, patients awaiting elective cardiac surgery need to be proactively managed, reprioritizing those with high-risk anatomy or whose clinical status is deteriorating. Finally, case volumes should be steadily increased in a mutually agreed upon fashion and must balance the clinical needs of patients awaiting surgery against the overall requirements of the health care system.

Cardiac Surgery in Canada During the COVID-19 Pandemic: A Guidance Statement From the Canadian Society of Cardiac Surgeons.

On March 11, 2020, the World Health Organization declared that COVID-19 was a pandemic.1 At that time, only 118,000 cases had been reported globally, 90% of which had occurred in 4 countries.1 Since then, the world landscape has changed dramatically. As of March 31, 2020, there are now nearly 800,000 cases, with truly global involvement.2 Countries that were previously unaffected are currently experiencing mounting rates of the novel coronavirus infection with associated increases in COVID-19-related deaths. At present, Canada has more than 8000 cases of COVID-19, with considerable variation in rates of infection among provinces and territories.3 Amid concerns over growing resource constraints, cardiac surgeons from across Canada have been forced to make drastic changes to their clinical practices. From prioritizing and delaying elective cases to altering therapeutic strategies in high-risk patients, cardiac surgeons, along with their heart teams, are having to reconsider how best to manage their patients. It is with this in mind that the Canadian Society of Cardiac Surgeons (CSCS) and its Board of Directors have come together to formulate a series of guiding statements. With strong representation from across the country and the support of the Canadian Cardiovascular Society, the authors have attempted to provide guidance to their colleagues on the subjects of leadership roles that cardiac surgeons may assume during this pandemic: patient assessment and triage, risk reduction, and real-time sharing of expertise and experiences.

Incidence of tamponade following temporary epicardial pacing wire removal.

BACKGROUND AND AIM OF STUDY: Placement of temporary epicardial pacing wires (TEPW) is common practice in cardiac surgery. Removal of TEPW in the postoperative period can lead to serious bleeding necessitating surgical intervention and conferring high morbidity. The purpose of this study is to determine the incidence of TEPW removal complications. METHODS: A retrospective review of all major cardiac operations at our institution from 2005 to 2016 was conducted. Patients were identified using the Maritime Heart Center Database. We reviewed preoperative, intra-operative, and postoperative characteristics of patients who returned to the operating room more than or equal to 3 days after their index operation to identify those who had bleeding and/or tamponade as a consequence of TEPW removal and any subsequent morbidity. RESULTS: A total of 11 754 patients underwent cardiac surgery at our institution between 2005 and 2016. Of these patients, 88 (0.75%) went back to the operating theater for bleeding and/or tamponade more than or equal to 3 days from their initial index operation. Of these, 11 (0.09%) were secondary to TEPW removal where two (0.017%) suffered irreversible anoxic brain injury. All 11 patients were on antiplatelet therapy with the addition of either deep venous thrombosis (DVT) prophylaxis or therapeutic anticoagulation, which is the standard of care at our institution. CONCLUSIONS: Bleeding complications following TEPW removal are rare but have significant consequences including increased hospital length of stay, resource utilization, and morbidity. Standardized practice to address antiplatelet, DVT prophylaxis, and anticoagulation before removal may help further reduce the incidence of serious bleeding events.

Impact of monoamine-related gene polymorphisms on hippocampal volume in treatment-resistant depression.

OBJECTIVE: In major depressive disorder (MDD), single nucleotide polymorphisms (SNPs) in monoaminergic genes may impact disease susceptibility, treatment response, and brain volume. The objective of this study was to examine the effect of such polymorphisms on hippocampal volume in patients with treatment-resistant MDD and healthy controls. Candidate gene risk alleles were hypothesised to be associated with reductions in hippocampal volume. METHODS: A total of 26 outpatients with treatment-resistant MDD and 27 matched healthy controls underwent magnetic resonance imaging and genotyping for six SNPs in monoaminergic genes [serotonin transporter (SLC6A4), norepinephrine transporter (SLC6A2), serotonin 1A and 2A receptors (HTR1A and HTR2A), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF)]. Hippocampal volume was estimated using an automated segmentation algorithm (FreeSurfer). RESULTS: Hippocampal volume did not differ between patients and controls. Within the entire study sample irrespective of diagnosis, C allele-carriers for both the NET-182 T/C [rs2242446] and 5-HT1A-1019C/G [rs6295] polymorphisms had smaller hippocampal volumes relative to other genotypes. For the 5-HTTLPR (rs25531) polymorphism, there was a significant diagnosis by genotype interaction effect on hippocampal volume. Among patients only, homozygosity for the 5-HTTLPR short (S) allele was associated with smaller hippocampal volume. There was no association between the 5-HT2A, COMT, and BDNF SNPs and hippocampal volume. CONCLUSION: The results indicate that the volume of the hippocampus may be influenced by serotonin- and norepinephrine-related gene polymorphisms. The NET and 5-HT1A polymorphisms appear to have similar effects on hippocampal volume in patients and controls while the 5-HTTLPR polymorphism differentially affects hippocampal volume in the presence of depression.

A Prospective, Longitudinal Study of the Effect of Remission on Cortical Thickness and Hippocampal Volume in Patients with Treatment-Resistant Depression.

BACKGROUND: Magnetic resonance imaging studies have provided evidence of structural modifications in cortical-limbic regions in major depressive disorder. To date, however, few studies have tracked structural changes in patients during treatment. This prospective, longitudinal imaging study investigated associations between brain structure and clinical responsiveness in a sample of patients with treatment-resistant major depressive disorder during an approximate 1-year follow-up period. METHODS: FreeSurfer software was used to extract volume or cortical thickness values from 6 regions of interest (hippocampus, rostral middle frontal gyrus, orbitofrontal cortex, rostral and caudal anterior cingulate cortices, and inferior temporal gyrus) in patients (n = 26) and matched healthy controls (n = 28). Regions of interest were selected based on previous evidence of potential associations between morphometric characteristics in these regions and treatment response or remission. Analyses were conducted to compare volume and cortical thickness in patients and controls at baseline imaging, determine whether patients' brain structure at treatment initiation was associated with response over follow-up, and compare longitudinal changes in volume and cortical thickness in patients who achieved sustained 6-month remission (Montgomery-Åsberg Depression Rating Scale Score ≤12) with nonremitters. RESULTS: Patients and controls showed no structural differences at baseline. Among patients, thicker right caudal anterior cingulate cortex at baseline was associated with greater symptom improvement over follow-up. Remitters and nonremitters showed subtle changes in volume and thickness over time in opposing directions, with increased hippocampal volume and cortical thickness in the rostral middle frontal gyrus, orbitofrontal cortex, and inferior temporal gyrus in remitters, and decreased volume or thickness in these regions in nonremitters. CONCLUSIONS: The results suggest that longitudinal structural trajectories may differ in major depressive disorder patients according to their clinical response to treatment.

Brain-volume increase with sustained remission in patients with treatment-resistant unipolar depression.

OBJECTIVE: Previous magnetic resonance imaging (MRI) studies have demonstrated brain-volume reductions in unipolar major depressive disorder (MDD). It is not clear whether these atrophic changes can be stabilized with antidepressant treatment and/or reversed with remission. The objective of this study was to prospectively examine brain-volume changes in patients with treatment-resistant depression, comparing those who achieved sustained remission with those who did not remit. METHOD: This prospective observational cohort study investigated the roles of clinical responsiveness and antidepressant treatment in lessening brain atrophy in depression. Data were collected between October 2004 and December 2008. Baseline MRI scans were obtained from 28 outpatients with treatment-resistant MDD (diagnosed according to DSM-IV criteria) who were recruited from the Mood Disorders Research Unit at the Royal Ottawa Mental Health Centre, Ottawa, Ontario, Canada. Twenty-seven patients underwent follow-up scanning after either 6 months of sustained remission (Montgomery-Asberg Depression Rating Scale score ≤ 12) or 12 months of failure to remit. Longitudinal whole-brain and voxel-based gray- and white-matter volume changes were estimated. RESULTS: Twelve patients (mean age at baseline = 47.5 years) achieved sustained 6-month remission. In contrast to nonremitters (n = 15; mean age at baseline = 44.3 years), remitted patients demonstrated a significant mean increase in whole-brain volume during follow-up (F(1,27) = 9.51, P = .005). Within-subject voxel-based morphometry analyses identified increased gray-matter volume in remitters in the right orbitofrontal cortex (t(11) = 7.61, P = .006) and the right inferior temporal gyrus (t(11) = 6.65, P = .004). Nonremitters showed decreased white-matter volume in the left anterior limb of the internal capsule (t(13) = 3.86, P = .04). CONCLUSIONS: Given that remitters exhibited a mean increase in brain volume while nonremitters lost volume, pharmacotherapy in the absence of sustained remission is most likely insufficient to elicit brain-volume increase in MDD. The findings suggest that clinical remission rather than pharmacotherapy may be the key factor involved in driving volumetric recovery in treatment-resistant depression.

[When a season means depression]. / Quand la saison devient synonyme de dépression.

Although becoming more and more recognized among physicians and psychiatrists the etiology of seasonal affective disorder (SAD) remains unclear. Indeed, the only incontestable fact is the close link between the decrease in sunlight occurring during fall and winter and the onset of depressive symptoms. But why does this seasonal decrease in the amount of light trigger a depression in some individuals while not affecting others? Why and how has sun exposure such an impact on brain-mood regulation? This review intends to shed some light on the main neurochemical hypotheses that have been advanced for the past 25 years. While several hypotheses have been advanced to explain SAD, the present review will focus on three major suspects which are: (1) melatonin due to its crucial role in circadian rhythms (2) serotonin which has been linked with depressive disorders in general and atypical symptoms and (3) catecholamine because as for serotonin, many data reported an implication of these neurotransmitter family in depressive disorders. However, similarly to other reviews about SAD, we conclude that none of those could explain the pathophysiology of this northern disease on its own.

Schizophrenia patients with polydipsia and water intoxication are characterized by greater severity of psychotic illness and a more frequent history of alcohol abuse.

Polydipsia and water intoxication (PWI) are relatively frequent among schizophrenic subjects, particularly in institutional settings and may lead to severe complications. However, little is known on their association with other characteristics of psychosis. Hence, we took advantage of a cohort of 114 subjects extensively assessed on natural history and clinical variables to examine the correlates of PWI in chronic schizophrenia. We randomly sampled DSM-IV schizophrenic subjects from: i) a lower functioning subgroup, i.e., long-term psychiatric wards or highly structured group housing facilities; and ii) a higher functioning subgroup, i.e., patients living in the community without supervision. Subjects were assessed from multiple sources for lifetime severity of positive, disorganisation, negative and depressive symptoms, premorbid adjustment, age of onset, level of functioning, comorbid diagnoses of substance abuse and lifetime history of PWI. Twelve subjects (10.5%) met our PWI criteria. We observed more severe psychotic symptoms, earlier onset, poorer current adjustment and more frequent prior alcohol use disorder in PWI subjects. When restricting comparisons to patients living in institutional setting, differences on clinical and natural history variables vanished but the association between PWI and prior alcohol abuse persisted (72.7% in PWI vs. 21.4% in non-PWI subjects, p<0.01). Onset of alcohol abuse predated the onset of PWI by a mean of 12.8 years. PWI schizophrenic subjects are characterized by a non-specific greater severity on a broad array of clinical and natural history variables and by a specific association with prior alcohol abuse. Thus, our data suggest that a greater severity of illness and a prior history of alcohol use disorders interact in increasing the risk of developing PWI in chronic schizophrenic patients.

Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study.

OBJECTIVE: Various classes of antidepressant medications generally induce remission of major depressive disorder in only about one-third of patients. In a previous study using mirtazapine or paroxetine alone or in combination from treatment initiation, the rate of patients who remitted within a 6-week period was twice that of patients using either drug alone. In this double-blind study, the authors sought to produce evidence for the superiority of different combinations of antidepressant drugs from treatment initiation. METHOD: Patients (N=105) meeting DSM-IV criteria for major depressive disorder were randomly assigned to receive, from treatment initiation, either fluoxetine monotherapy (20 mg/day) or mirtazapine (30 mg/day) in combination with fluoxetine (20 mg/day), venlafaxine (225 mg/day titrated in 14 days), or bupropion (150 mg/day) for 6 weeks. The primary outcome measure was the Hamilton Depression Rating Scale (HAM-D) score. RESULTS: The overall dropout rate was 15%, without notable differences among the four groups. Compared with fluoxetine monotherapy, all three combination groups had significantly greater improvements on the HAM-D. Remission rates (defined as a HAM-D score of 7 or less) were 25% for fluoxetine, 52% for mirtazapine plus fluoxetine, 58% for mirtazapine plus venlafaxine, and 46% for mirtazapine plus bupropion. Among patients who had a marked response, double-blind discontinuation of one agent produced a relapse in about 40% of cases. CONCLUSIONS: The combination treatments were as well tolerated as fluoxetine monotherapy and more clinically effective. The study results, which add to a growing body of evidence, suggest that use of antidepressant combinations from treatment initiation may double the likelihood of remission compared with use of a single medication.

Evidence of a biological effect of light therapy on the retina of patients with seasonal affective disorder.

BACKGROUND: Retinal sensitivity anomalies have been reported in patients affected by seasonal affective disorder (SAD). We used the electroretinogram (ERG) to assess seasonal change in retinal function in patients with SAD and healthy participants, as well as in patients following 4 weeks of light therapy. METHODS: ERG assessments were obtained in 22 SAD patients (2 men, 20 women, mean age 31 +/- 9 years) in the fall/winter season before and after 2 and 4 weeks of light therapy and in summertime. Matched healthy participants (2 men, 14 women; mean age 29 +/- 8 years) were evaluated once in the fall/winter and once in summer. The 29-item Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder version was administered. Standard ERG parameters were derived from the photopic and scotopic luminance response functions. Salivary melatonin concentration during ERG was assessed in both groups but during fall/winter assessments only. RESULTS: A significantly lower cone ERG maximal amplitude and lower rod sensitivity was found in SAD patients before light therapy compared with healthy participants. Following 4 weeks of light therapy, a normalization of cone and rod ERG function occurred. ERG parameters in the summer and melatonin concentrations in fall/winter were not significantly different between groups. CONCLUSIONS: Depressed patients with SAD demonstrate ERG changes in the winter compared with healthy comparison subjects with lower rod retinal sensitivity and lower cone maximal amplitude. These changes normalized following 4 weeks of light therapy and during the summer, suggesting that ERG changes are state markers for SAD.

Physiologic mechanisms underlying the antidepressant discontinuation syndrome.

The rate at which serotonin reuptake inhibitor (SRI) treatment is terminated and the duration of treatment appear to be key factors in predicting discontinuation symptoms. The development of animal models to explain the mechanisms of this clinical problem has proved challenging, because less than half of all patients experience any discontinuation symptoms, many of which are subjective in nature. One explanation is that SRI discontinuation symptoms may arise from the rapid decrease in serotonin (5-HT) availability when treatment ends abruptly. Yet, it would appear that discontinuation discomforts may not be mediated exclusively through 5-HT receptors, given the major regulatory role 5-HT exerts on a number of specific chemical receptor systems in the brain. As a result, attempts to explain the determinants of this phenomenon rely on a certain level of speculation. This article examines the possible physiologic bases for the antidepressant discontinuation syndrome and briefly describes these adaptations. It discusses the 3 systems most likely to account for at least part of the symptomatology--the 5-HT, the norepinephrine, and the cholinergic systems--and the possible interactions among them. It also attempts to explain their implications in the therapeutic actions of antidepressants in patients with affective and anxiety disorders.

Catecholaminergic strategies for the treatment of major depression.

Although the selective serotonin reuptake inhibitors have become the first line medications for the treatment of depression, drugs primarily targeting the norepinephrine (NE) and/or the dopamine catecholaminergic systems are also effective. These include selective NE reuptake inhibitors, such as desipramine and reboxetine, the NE releaser bupropion and the alpha2-adrenergic antagonists mianserin and mirtazapine. Dopamine type 2 agonists are also effective in treating depression, although they are rarely used. Since the NE, dopamine and serotonin systems have reciprocal interactions, it is virtually impossible to act on a specific neuronal element without affecting in a cascade effect the two other systems. In this review, the primary actions of the catecholaminergic strategies upon their acute and long-term administration are described, as well as their impact on other systems. Their use in treatment-resistant depressed patients is also addressed.

Characterization of type 12 17beta-hydroxysteroid dehydrogenase, an isoform of type 3 17beta-hydroxysteroid dehydrogenase responsible for estradiol formation in women.

A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. Both are encoded by large genes spanning 11 exons, most of them showing identical size. Using human embryonic kidney-293 cells stably expressing 17beta-HSD12, we have found that the enzyme catalyzes selectively and efficiently the transformation of E1 into E2, thus identifying its role in estrogen formation, in contrast with 17beta-HSD3, the enzyme involved in the biosynthesis of the androgen testosterone in the testis. Using real-time PCR to quantify mRNA in a series of human tissues, the expression levels of 17beta-HSD12 as well as two other enzymes that perform the same transformation of E1 into E2, namely type 1 17beta-HSD and type 7 17beta-HSD, it was found that 17beta-HSD12 mRNA is the most highly expressed in the ovary and mammary gland. To obtain a better understanding of the structural basis of the difference in substrate specificity between 17beta-HSD3 and 17beta-HSD12, we have performed tridimensional structure modelization using the coordinates of type 1 17beta-HSD and site-directed mutagenesis. The results show the potential role of bulky amino acid F234 in 17beta-HSD12 that blocks the entrance of androstenedione. Overall, our results strongly suggest that 17beta-HSD12 is the major estrogenic 17beta-HSD responsible for the conversion of E1 to E2 in women, especially in the ovary, the predominant source of estrogens before menopause.