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Prediction of treatment outcomes is a key step in improving the treatment of major depressive disorder (MDD). The Canadian Biomarker Integration Network in Depression (CAN-BIND) aims to predict antidepressant treatment outcomes through analyses of clinical assessment, neuroimaging, and blood biomarkers.
In the CAN-BIND-1 dataset of 192 adults with MDD and outcomes of treatment with escitalopram, we applied machine learning models in a nested cross-validation framework. Across 210 analyses, we examined combinations of predictive variables from three modalities, measured at baseline and after 2 weeks of treatment, and five machine learning methods with and without feature selection. To optimize the predictors-to-observations ratio, we followed a tiered approach with 134 and 1152 variables in tier 1 and tier 2 respectively.
A combination of baseline tier 1 clinical, neuroimaging, and molecular variables predicted response with a mean balanced accuracy of 0.57 (best model mean 0.62) compared to 0.54 (best model mean 0.61) in single modality models. Adding week 2 predictors improved the prediction of response to a mean balanced accuracy of 0.59 (best model mean 0.66). Adding tier 2 features did not improve prediction.
A combination of clinical, neuroimaging, and molecular data improves the prediction of treatment outcomes over single modality measurement. The addition of measurements from the early stages of treatment adds precision. Present results are limited by lack of external validation. To achieve clinically meaningful prediction, the multimodal measurement should be scaled up to larger samples and the robustness of prediction tested in an external validation dataset.
This article is a clinical guide which discusses the “state-of-the-art” usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion—this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy—while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward “bridging” methods that may be used to transition simply and safely from other antidepressants to MAOIs.
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.
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).
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.
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.
The treatment of major depression remains problematic for several reasons. In particular, the therapeutic response to medications usually does not manifest itself until a week after administration has begun, and more than half the patients will not experience a full recovery with the first antidepressant drug administration. There are, however, some pharmacologic strategies that can accelerate antidepressant response. When facing a treatment-resistant depression, combination therapy offers a more time-efficient approach to achieve remission than drug substitution. These interventions have been devised on a better understanding of the basis for the therapeutic response obtained with the first- and second-generation antidepressants, and evidence derived from controlled clinical trials of their superior effectiveness is growing. The rationale for such approaches will be described in this article, as well as their advantages and potential inconveniences. Ongoing research in this field continues to fuel the development of novel, better-tolerated, and more effective pharmacotherapies for depression.
Obsessive-compulsive disorder (OCD) experienced in childhood or adolescence is often a chronic disorder with high subjective distress and impairment of family and social functioning. An early comprehensive intervention schedule can have a profound effect on outcome in later years. The clinical manifestations of OCD among children and adolescents do not seem to be inherently different from those of adult patients. In younger subjects, the clinical picture tends to be dominated by compulsions, and insight can be poor, with little recognition of the symptoms as a problem.There is often a shift in symptoms over time, with some symptoms being replaced by others, while in adults, the core obsessions and compulsions tend to be more stable. In addition to depression and anxiety disorders, the spectrum of comorbid psychopathology seen in pediatric OCD patients includes tic, disruptive behavior, and specific developmental disorders. The treatment of childhood and adolescent OCD relies on cognitive-behavioral techniques of psychotherapy and pharmacotherapeutic interventions similar to those recommended in adults. The efficacy of exposure and response prevention in pediatric OCD has been shown in numerous open studies, and four controlled trials. Pharmacotherapy relies on serotonergic medication, and all have been demonstrated to be significantly superior to placebo, as reported in a recently published meta-analysis. Current concerns with the use of SSRIs in children and adolescents were explored as regards OCD and anxiety disorders, and there is no evidence for an increase in suicide or related behaviors.
Environmental stimuli and drugs affect the norepinephrine (NE) system and may be linked to the manifestation and treatment of anxiety and affective disorders. The activity of locus ceruleus NE neurons in the brainstem can alter the function offorebrain structures associated with several psychiatric disorders. In particular, NE neurons send and receive projections from sensory afferents, limbic areas, and cortical areas implicated in higher-order brain malfunctions and the symptomatology of anxiety and affective disorders. In turn, anxiolytic and antidepressant drugs are able to offset perturbations of NE activity and forebrain structures with a time course congruent with their therapeutic action. All antide-pressants, even the agents selective for other biogenic amines or peptides, act on the NE system. In the present review, the effects of antidepressants on NE neurons are summarized and applied to the treatment of neuropsychiatric disorders, with emphasis placed on mechanisms of action.
Most antidepressants and other psychotropics in clinical use are available as generic formulations (Table). The availability of lower-priced, generic drugs can benefit patients and third-party payers, but it should not be assumed that all generic drugs are equally beneficial. There are numerous reports in the literature of unexpected and untoward consequences that occur when a generic drug is substituted for the original brand-name drug. A previously stable clinical response may suddenly deteriorate, or the patient may experience new or more severe adverse events (AEs). The United States Food and Drug Administration requires that manufacturers of generic drugs demonstrate that their formulation has pharmacokinetic properties similar (or bioequivalent) to the brand-name drug. Bioequivalency studies are conducted in healthy volunteers, not in patients who would be treated with that drug. Moreover, bioequivalency studies are conducted on a current lot of the branded drug and do not account for variability between lots of the generic formulation. The manufacturer is only required to submit bioequivalency data that support the Abbreviated New Drug Application (ANDA); the FDA does not require disclosure of failed bioequivalence studies. Unlike brand-name drugs, lengthy and costly clinical studies are not required to show that the generic drug is effective and safe.
Although the FDA has taken the position that bioequivalence and therapeutic equivalence are equal, many questions related to the use of generic drugs remain unanswered. The following question-and-answer session is an excerpt of an interview with Pierre Blier, MD, PhD, conducted by Diane Sloan, PharmD, which addresses the issue of generic substitution of psychotropic drugs.
This is the first report of early-life developmental characteristics (coloration pattern, growth and survival) and genetic identification of the wolffish interspecific hybrid between Anarhichas minor and A. lupus, both endangered species in Canadian coastal water and of interest for cold-water aquaculture diversification.
A first growth trial at 8 °C featuring pure strains A. minor and the hybrid
A. minor × A. lupus in triplicates was conducted in 2006 during the period from 0 to 140 days post-hatch. A second growth trial was runned in 2007 featuring A. minor, A. lupus and the reciprocal hybrids A. minor × A. lupus and A. lupus × A. minor. Egg development indicators and early-hatching characteristics are reported.
Over the last 25 years, the perception of obsessive-compulsive disorder (OCD) has changed; where once it was seen as a rare refractory disorder, it is now viewed as a fairly prevalent, but treatable, medical condition responding to two main therapeutic strategies–serotonin reuptake inhibitors (SRIs) and cognitive-behavioral therapy (CBT). Given the emergence of new results with SRIs, more data on the role of augmentation strategies with second-generation antipsychotics, and recent genetic and neuroimaging findings with potential for advancing the understanding of the pathogenesis of OCD, it was thought appropriate to revisit OCD in order to identify key developments in this field and examine how they might be translated into the clinical arena. This consensus statement is the product of the International Anxiety Disorders Conference that took place in Cape Town in February 2006, and is referred to as the Cape Town Consensus (CTC).
In the Diagnostic and Statistical Manual of Mental Disorders (DSM) system, OCD has been classified as an anxiety disorder. However, in the International Classification of Diseases (ICD) system, OCD is separated from these conditions. This is consistent with several findings. OCD can begin before puberty, whereas other anxiety disorders, particularly generalized anxiety disorder (GAD), have a later age of onset. OCD is similarly prevalent in men and women, as opposed to depressive and anxiety disorders, which are more common in women. Pharmacologic challenges in some (but not all) studies show exacerbation of symptoms to 5-HT receptor agonists (eg, mCPP, sumatriptan), but not to other anxiogenic challenges such as yohimbine, sodium lactate, caffeine, CO2, cholecystokinin, and pentagastrin, which are known to elicit anxiety symptoms in anxiety disorders.
The intraspecific variation in the number and distribution of paragnaths in ten populations of Nereis (Neanthes) virens collected throughout its range was examined. Significant differences among populations are found in the total number of paragnaths and in each paragnath group. The unweighted pair-group method using arithmetic averages cluster analysis revealed three distinct clusters separating Canadian populations, Europe/USA populations and the Japanese population, suggesting the implication of either restricted gene flow, selection on paragnath patterns or phenotypic plasticity. Comparison with a previous genetic study suggests that morphological variants represent ecotypes of the single, widely distributed N. virens species.
We tested the hypothesis that along with gill Na+K+ATPase activity reduction, branchial energetic metabolism of brook charr (Salvelinus fontinalis) is altered during sexual maturation. Maturing and sterile fish were transferred from freshwater (FW) to seawater (SW). The activity of gill pyruvate kinase (PK), cytochrome C oxidase (COX), citrate synthase (CS) and lactate dehydrogenase (LDH) was measured at different intervals. Following 1 month in SW, twofold increases in Na+K+ATPase activity were recorded in all groups, while mean metabolic enzyme activities were sharply reduced (COX: 0.051 ± 0.029 to 0.036 ± 0.018; PK: 1.670 ± 0565 to 1.210 ± 0.340 LDH: 2.245 ± 0.690 to 1.642 ± 0.381 μmol mg–1 protein min–1). Interestingly, during this period, no mortality occurred. After 5 months, comparison of Na+K+ATPase:CS and Na+K+ATPase:LDH ratios of mature and sterile fish held either in FW or SW, indicated that the response of Na+K+ATPase largely exceeds the response of the metabolic enzyme apparatus in hyperosmotic conditions. Hence, the reduced iono-osmoregulatory capacity and higher mortality observed in SW-maturing fish during the reproductive season appears to be mainly attributable to Na+K+ATPase activity reduction rather than the alteration of gill metabolic capacity, since no concurrent increase of metabolic enzyme activity with Na+K+ATPase activity occurred.
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