Subset Of Depressed Patients Research Articles

Rapid-acting antidepressants and the circadian clock.

A growing number of epidemiological and experimental studies has established that circadian disruption is strongly associated with psychiatric disorders, including major depressive disorder (MDD). This association is becoming increasingly relevant considering that modern lifestyles, social zeitgebers (time cues) and genetic variants contribute to disrupting circadian rhythms that may lead to psychiatric disorders. Circadian abnormalities associated with MDD include dysregulated rhythms of sleep, temperature, hormonal secretions, and mood which are modulated by the molecular clock. Rapid-acting antidepressants such as subanesthetic ketamine and sleep deprivation therapy can improve symptoms within 24 h in a subset of depressed patients, in striking contrast to conventional treatments, which generally require weeks for a full clinical response. Importantly, animal data show that sleep deprivation and ketamine have overlapping effects on clock gene expression. Furthermore, emerging data implicate the circadian system as a critical component involved in rapid antidepressant responses via several intracellular signaling pathways such as GSK3β, mTOR, MAPK, and NOTCH to initiate synaptic plasticity. Future research on the relationship between depression and the circadian clock may contribute to the development of novel therapeutic strategies for depression-like symptoms. In this review we summarize recent evidence describing: (1) how the circadian clock is implicated in depression, (2) how clock genes may contribute to fast-acting antidepressants, and (3) the mechanistic links between the clock genes driving circadian rhythms and neuroplasticity.

Replicable association between human cytomegalovirus infection and reduced white matter fractional anisotropy in major depressive disorder

Major depressive disorder (MDD) is associated with reductions in white matter microstructural integrity as measured by fractional anisotropy (FA), an index derived from diffusion tensor imaging (DTI). The neurotropic herpesvirus, human cytomegalovirus (HCMV), is a major cause of white matter pathology in immunosuppressed populations but its relationship with FA has never been tested in MDD despite the presence of inflammation and weakened antiviral immunity in a subset of depressed patients. We tested the relationship between FA and HCMV infection in two independent samples consisting of 176 individuals with MDD and 44 healthy controls (HC) (Discovery sample) and 88 participants with MDD and 48 HCs (Replication sample). Equal numbers of HCMV positive (HCMV+) and HCMV negative (HCMV−) groups within each sample were balanced on ten different clinical/demographic variables using propensity score matching. Anti-HCMV IgG antibodies were measured using a solid-phase ELISA. In the Discovery sample, significantly lower FA was observed in the right inferior fronto-occipital fasciculus (IFOF) in HCMV+ participants with MDD compared to HCMV− participants with MDD (cluster size 1316 mm3; pFWE < 0.05, d = −0.58). This association was confirmed in the replication sample by extracting the mean FA from this exact cluster and applying the identical statistical model (p < 0.05, d = −0.45). There was no significant effect of diagnosis or interaction between diagnosis and HCMV in either sample. The effect of chronic HCMV infection on white matter integrity may—in at-risk individuals—contribute to the psychopathology of depression. These findings may provide a novel target of intervention for a subgroup of patients with MDD.

Does Arginine Vasopressin Reflect HPA-axis Activation in Major Depressive Disorder?

Researchers have endeavored to subclassify depressive illness based on pathophysiological mechanism. One model relates to hypothalamic-pituitary-adrenal (HPA) axis overactivation with a shift from corticotropin-releasing hormone (CRH) driven regulation to arginine vasopressin (AVP) driven regulation. Given the mixed literature, we compared plasma AVP levels in healthy controls to patients with major depressive disorder (MDD). Plasma samples from 33 patients and 12 controls were collected at baseline, 8 weeks, and 12 weeks of treatment and measured by immunochemical assay. Patients who were treatment responders trended toward lower AVP levels than non-responders. Patients were stratified into low and high AVP groups based on median split. Within the low AVP group, patients whose current episode lasted longer than a year had significantly higher baseline AVP levels than patients whose current episode was less than 6 months. Female patients in the low AVP group had significantly higher baseline AVP levels than male patients. Given the association between stress, HPA axis activation, immune dysregulation, and depression, we also measured concentrations of inflammatory biomarkers. We found a significant negative correlation between IL-10 and baseline AVP levels, within the low AVP subgroup. Given inconsistent data, HPA axis overactivation may be present within a subset of depressed patients.

Antidepressants of different classes cause distinct behavioral and brain pro- and anti-inflammatory changes in mice submitted to an inflammatory model of depression

BackgroundDepressed patients present increased plasma levels of lipopolysaccharide (LPS) and neuroinflammatory alterations. Here, we determined the neuroimmune effects of different classes of ADs by using the LPS inflammatory model of depression. MethodsMale rats received amitriptyline (AMI) a tricyclic, S-citalopram (ESC) a selective serotonin reuptake inhibitor, tranylcypromine (TCP) a monoamine oxidase inhibitor, vortioxetine (VORT) a multimodal AD or saline for ten days. One-hour after the last AD administration, rats were exposed to LPS 0.83 mg/kg or saline and 24 h later were tested for depressive-like behavior. Plasma corticosterone, brain levels of nitrite, pro- and anti-inflammatory cytokines, phospho-cAMP Response Element-Binding Protein (CREB) and nuclear factor (NF)-kB p 65 were determined. ResultsLPS induced despair-like, impaired motivation/self-care behavior and caused anhedonia. All ADs prevented LPS-induced despair-like behavior, but only VORT rescued impaired self-care behavior. All ADs prevented LPS-induced increase in brain pro-inflammatory cytokines [interleukin (IL)-1β and IL-6] and T-helper 1 cytokines [tumor necrosis factor (TNF)-α and interferon-γ]. VORT increased striatal and hypothalamic IL-4 levels. All ADs prevented LPS-induced neuroendocrine alterations represented by increased levels of hypothalamic nitrite and plasma corticosterone response. VORT and ESC prevented LPS-induced increase in NF-kBp65 hippocampal expression, while ESC, TCP and VORT, but not IMI, prevented the alterations in phospho-CREB expression. LimitationsLPS model helps to understand depression in a subset of depressed patients with immune activation. The levels of neurotransmitters were not determined. ConclusionThis study provides new evidence for the immunomodulatory effects of ADs, and shows a possible superior anti-inflammatory profile of TCP and VORT.

Magnetic Seizure Therapy: an Evolution of Convulsive Therapy

Purpose of Review Treatment-resistant depression (TRD) affects a significant subset of depressed patients. It is estimated that about 30 % of patients with major depressive disorder do not respond to standard treatments. For these patients, electroconvulsive therapy (ECT) remains the most effective treatment despite being limited by its side effects. Modifications to ECT parameters have suggested that it may be possible to separate the therapeutic effects of convulsive therapy from the production of side effects.

The role of IL18-607C > A and IL18-137G > C promoter polymorphisms in antidepressant treatment phenotypes: A preliminary report

Recent studies suggest that immune activation and cytokines, such as IL-18, are involved in depression. IL-18 is expressed in brain and is increased in patients with moderate to severe depression. In this study we aim to evaluate the role of IL18-607C>A and IL18-137G>C promoter polymorphisms in antidepressant treatment phenotypes, specifically relapse and treatment resistant depression (TRD). We genotyped the referred polymorphisms in a subset of 80 MDD patients followed at Hospital Magalhães Lemos, Portugal, within a period of 27 months. Patients carrying IL18-607 CA or AA genotypes were significantly more prone to relapse after AD treatment and present a significantly lower time to relapse than patients carrying CC genotype. Similarly, patients carrying IL18-137 GC or CC genotypes have a significantly higher risk of relapse and display relapse significantly earlier than the ones carrying GG genotype. Due to the low number of IL18-607 CC and IL18-137 GG in the relapse subgroup (n=3 and n=5, respectively), results were validated by bootstrapping analysis, and remained significant. No association was found between the evaluated genetic polymorphisms and TRD. IL18 peripheral mRNA levels were upregulated in IL18-607 CA or AA carriers. This preliminary report indicates that IL18-607C>A and IL18-137G>C genetic polymorphisms seem to influence depression relapse after antidepressant treatment in our subset of depressed patients, and may possibly contribute to the disregulated IL-18 levels found in patients with depression.

Transcriptomics and the mechanisms of antidepressant efficacy

The mechanisms by which antidepressants have their effects are not clear and the reasons for variability in treatment outcomes are also unknown. However, there is evidence from candidate gene research that indicates gene expression changes may be involved in antidepressant action. In this study, we examined antidepressant-induced alterations in gene expression on a transcriptome-wide scale, exploring associations with treatment response. Blood samples were taken from a subset of depressed patients from the GENDEP study (n=136) before and after eight weeks of treatment with either escitalopram or nortriptyline. Transcriptomic data were obtained from these samples using Illumina HumanHT-12 v4 Expression BeadChip microarrays. When analysing individual genes, we observed that changes in the expression of two genes (MMP28 and KXD1) were associated with better response to nortriptyline. Considering connectivity between genes, we identified modules of genes that were highly coexpressed. In the whole sample, changes in one of the ten identified coexpression modules showed significant correlation with treatment response (cor=0.27, p=0.0029). Using transcriptomic approaches, we have identified gene expression correlates of the therapeutic effects of antidepressants, highlighting possible molecular pathways involved in efficacious antidepressant treatment.

Influence of Il-18 Genetic Polymorphisms in Antidepressant Treatment Phenotypes

Introduction Recent studies suggested that immune activation and cytokines might be involved in depression. The proinflammatory cytokine interleukin-18 (IL-18) is less reported in depression but is still relevant since it is expressed in the brain and serum levels of IL-18 have been found to be increased in patients with moderate to severe depression. Therefore, it seems reasonable that IL-18 promoter SNPs may have an effect in antidepressant response phenotypes. Objectives We aim to evaluate the role of IL18-607C>A and IL18-137G>Cpromoter polymorphisms in antidepressant treatment phenotypes, specifically remission, relapse and treatment resistant depression (TRD). Methods We genotyped the referredpolymorphisms in a subset of 80 MDD patients followed at Hospital Magalhaes Lemos, Portugal, within a period of 27 months. Results We found that patients carrying IL18-607CA or AA genotypes are more prone to relapse after AD treatment (OR=4.145; 95%CI: [1.038-16.555]; p=0.043) and present a lower time to relapse than patients carrying CC genotype (69 vs 115 weeks, p=0.019, Log-rank test). We also observed that patients carrying IL18-137GC or CC genotypes have a higher risk of relapse (OR=3.988; 95%CI: [1.176-13.516]; p=0.022) and display relapse earlier than the ones carrying GG genotype (64 vs 112 weeks, p=0.006, Log-rank test). No association was found between the evaluated genetic polymorphisms and remission or TRD. Conclusions The IL18-607A>C and IL18-137G>Cpolymorphisms seems to influence relapse after antidepressant treatment in our subset of depressed patients. These polymorphisms may possibly contribute to the elevated IL-18 levels found in patients with moderate to severe depression.

Cytisine and diarylpropionitrile may not modulate depressive behaviors in female WKY rats

Event Abstract Back to Event Cytisine and diarylpropionitrile may not modulate depressive behaviors in female WKY rats Praveen Kandi1, Joseph Tanga1 and Renee L. Hayslett1* 1 Mercer University, College of Pharmacy and Health Sciences, United States Nicotine and estrogen may regulate mood and influence depressive behaviors. Results from rodent studies suggest the potential involvement of nicotinic cholinergic receptors and estrogen receptors in antidepressant-like behavior. Specifically, blockade of nicotinic receptors containing the β2 subunit may be responsible for antidepressant effects [1]. Furthermore, selective estrogen receptor β (ERβ) agonists have been shown to reduce depressive behaviors in female ovariectomized rats [2]. In this study, we evaluated potential anti-anxiety and anti-depressant effects of a nicotinic agent, cytisine, and a selective estrogen receptor modulator, diarylpropionitrile (DPN), in an animal model of depression in female rats. Cytisine is a partial agonist at α4β2 receptors and a full agonist at α3β4 and α7 receptors. DPN is a selective ERβ agonist. The Wistar Kyoto (WKY) rat strain is a putative model of endogenous depression. Compared to their control, the Wistar rat, WKY rats demonstrate hormonal, behavioral and physiological parameters that are similar to symptoms found in depressed patients [3]. WKY rats appear to be resistant to standard SSRI antidepressants. Interestingly, a subset of depressed patients does not respond to SSRI drugs. Therefore, this model could be useful in identifying novel agents for antidepressant therapy. Female WKY and Wistar rats (n=6-8/group) received subcutaneous injections of cytisine (0.5, 1, 1.5 mg/kg), DPN (10 μg, 0.5 mg/kg, 1 mg/kg) or vehicle prior to being tested in the elevated plus maze (EPM), locomotor activity chamber (LCA) and forced swim test (FST). Dosages and latencies for drug administration were chosen based on previous reports and data from preliminary studies. Our results show that WKY rats displayed significantly more depressive behaviors compared to Wistar rats. WKY rats had significantly more immobility counts and also significantly less locomotor activity compared to Wistar rats. No differences were detected in the EPM with cytisine or DPN in either strain. In addition, none of the doses of DPN produced significant effects on behavior in the other tested paradigms. Because the rats had intact reproductive systems, their behavior could be influenced by the estrous cycle. At the tested doses of cytisine, the 1.5 mg/kg dose significantly increased immobility in the FST in Wistar and WKY rats. There was a trend for WKY rats treated with 1.5 mg/kg of cytisine to exhibit reduced locomotor activity; however, this did not reach statistical significance. At this dose of cytisine there appears to be an exaggeration of depressive behaviors. This observation could be due to activation of nicotinic receptors in the peripheral ganglia, which may cause autonomic dysregulation and account for the decrease of locomotor activity and increase in immobility in the FST. In conclusion, cytisine and DPN do not appear to have anti-anxiety or anti-depressant effects in the female WKY rat. Additional experiments that test a wider range of doses, combination of drugs, and consider the phase of estrous cycle are necessary.

PP86 Sister chromatid exchanges as marker of genomic instability in familial breast cancer patients

The mechanisms by which antidepressants have their effects are not clear and the reasons for variability in treatment outcomes are also unknown. However, there is evidence from candidate gene research that indicates gene expression changes may be involved in antidepressant action. In this study, we examined antidepressant-induced alterations in gene expression on a transcriptome-wide scale, exploring associations with treatment response. Blood samples were taken from a subset of depressed patients from the GENDEP study (n=136) before and after eight weeks of treatment with either escitalopram or nortriptyline. Transcriptomic data were obtained from these samples using Illumina HumanHT-12 v4 Expression BeadChip microarrays. When analysing individual genes, we observed that changes in the expression of two genes (MMP28 and KXD1) were associated with better response to nortriptyline. Considering connectivity between genes, we identified modules of genes that were highly coexpressed. In the whole sample, changes in one of the ten identified coexpression modules showed significant correlation with treatment response (cor=0.27, p=0.0029). Using transcriptomic approaches, we have identified gene expression correlates of the therapeutic effects of antidepressants, highlighting possible molecular pathways involved in efficacious antidepressant treatment.

Treatment-Associated Suicidal Ideation and Adverse Effects in an Open, Multicenter Trial of Fluoxetine for Major Depressive Episodes

Background: Some reports suggest that a subset of depressed patients may experience suicidality – that is increase or emergence of suicidal ideation (SI) or behavior – after initiation of an antidepressant. The time course and clinical correlates of this phenomenon have not been characterized in detail. Method: We conducted a secondary analysis of a multicenter, prospective, open, 12-week trial of fluoxetine 20 mg in outpatients with nonpsychotic major depressive episodes. Adverse effects and other clinical features associated with the emergence of suicidality, defined using item 3 of the Hamilton Depression Rating Scale, were examined using Cox regression models. Results: Among 414 subjects without SI at baseline, 59 (14.3%) reported SI on at least 1 postbaseline visit. In a Cox regression, emergence of activation and worsening of depression severity were independently associated with emergence of SI, along with female gender, younger age and having thoughts that life was not worth living prior to treatment. Treatment response and remission were significantly less likely among subjects who developed SI. Conclusions: New SI was relatively common in this trial of fluoxetine and associated with the emergence of activation and overall symptomatic worsening. Whether prophylaxis against or aggressive treatment of adverse events can decrease emergence of SI merits further study.

Depression and smoking: examining correlates in a subset of depressed patients.

The objective of this study was to examine for associations between depression and cigarette smoking. A sample of 92 depressed smokers was compared with a control sample of depressed non-smokers, matched for age, gender and diagnostic variables. Comparisons were made across a range of demographic, depression, family history, developmental factors, anxiety and personality style variables, as well as use of alcohol and illicit drugs. We failed to find any difference between smokers and non-smokers in history or severity of depression. Cigarette smokers were distinguished principally by greater exposure to aversive experiences in childhood, disordered personality function, greater use of illicit drugs, anxiolytics and alcohol. Logistic regression identified dysfunctional personality 'domains', physical violence in childhood, long-term anxiolytic use and illicit drug use as the most significant predictor set. Results favour a model of cigarette smoking and depression as linked by shared early deprivational variables, rather than cigarette smoking causing depression or the converse.

Immunodetection and quantitation of imidazoline receptor proteins in platelets of patients with major depression and in brains of suicide victims.

Imidazoline receptors are a newly discovered family of receptors, some of which, like alpha 2-adrenoceptors, have a presynaptic inhibitory effect on the release of norepinephrine. The aim of this study was to identify by immunodetection imidazoline receptor proteins in human platelets and the brain to assess their status in depression and suicide. Platelets were collected from 26 drug-free depressed patients and 26 controls. Specimens of frontal cortex (Brodmann area 9) were collected from 13 suicide victims and 11 controls. Levels of imidazoline receptor proteins were assessed by immunoblotting techniques. Solubilized imidazoline receptors were separated by gel electrophoresis, transferred to nitrocellulose membranes, labeled with a specific anti-imidazoline receptor antiserum, and quantitated by image analysis. Platelet and brain membranes expressed similar 45-kd imidazoline receptor proteins, and their mean +/- SEM immunoreactivities were found to be increased in depressed patients (platelets, 40% +/- 5%) and suicide victims (brain, 51% +/- 14%). Platelets also expressed a 35-kd imidazoline receptor protein that was also found to be up-regulated in depressed patients (21% +/- 4%). In contrast, brain membranes did not express this 35-kd protein but revealed a 29/30-kd imidazoline receptor protein that was found to be down-regulated in suicide victims (19% +/- 3%). In a subset of depressed patients who underwent antidepressant treatment, a change in the immunoreactivity of the up-regulated 45-kd platelet imidazoline receptor protein (-35% +/- 5%), but not of the 35-kd protein, was observed. The results support a role for the newly discovered imidazoline receptors (mainly the 45-kd receptor expressed in the brain and platelets) in the pathogenesis of depression.

Neuropathological correlates of psychotic phenomena in confirmed Alzheimer's disease.

The prevalence of psychotic phenomena in confirmed Alzheimer's disease (AD) and their potential neuropathological correlates have rarely been the subject of prospective investigation. Psychopathological disturbances were recorded prospectively according to the Geriatric Mental State Schedule and the CAMDEX: The frequency of these phenomena and neuropathological changes were examined in 56 patients with definite AD. Hallucinations had been documented in 13 patients, paranoid delusions in 9 and delusional misidentification (e.g. the Capgras-type and the 'phantom boarder' symptoms) in 14 patients. Misidentifications were associated with lower neurone counts in the area CA1 of the hippocampus. Delusions and hallucinations were observed in patients with less severe cell loss in the parahippocampal gyrus and with lower cell counts in the dorsal raphe nucleus. A decrease of neurones in the locus coeruleus in a subset of depressed patients with AD had been reported earlier. Delusions and delusional misidentification were common in 5 patients with basal ganglia mineralisation, but there was no statistically significant association of these symptoms with the presence of Lewy bodies in the brainstem and neocortex of our patient sample. These findings are compatible with the view that morphological changes in certain brain areas may promote the development of psychotic phenomena in AD. AD may offer a model for the understanding of pathomechanisms underlying the development of psychopathological disturbances in other psychoses with more discrete neuropathological changes.

Anger attacks in unipolar depression, Part 2: Neuroendocrine correlates and changes following fluoxetine treatment.

Neuroendocrine derangements have been reported in both depression and aggressive behavior. The purpose of this study was to evaluate whether the subset of depressed patients with anger attacks have a distinctive neuroendocrine abnormality. The thyrotropin-releasing hormone (TRH) test was administered to 25 patients with major depression, 12 of whom reported having anger attacks, at the Depression Research Program of the Clinical Psychopharmacology Unit at the Massachusetts General Hospital. Twenty-two subjects underwent the TRH test again after 8 weeks of treatment with fluoxetine, a relatively selective serotonin uptake inhibitor. The depressed patients with anger attacks had a blunted prolactin response to TRH stimulation compared to the depressed patients without anger attacks. Treatment with fluoxetine was followed by an overall increase in the prolactin response to TRH among the depressed patients with anger attacks. The prolactin response to TRH also tended to predict the degree of response to treatment. These results suggest that the subset of depressed patients with anger attacks may have a greater central serotonergic dysregulation than depressed patients without such attacks.

Primary depressives with secondary alcoholism compared with alcoholics and depressives

While a subset of depressed patients are believed to “self-medicate” their depression with alcohol, there are no studies comparing the phenomenological and diagnostic characteristics of patients with primary depression and secondary alcoholism with those of patients with depression or alcoholism alone. In this study, we compared 11 patients from each of these three diagnostic groups in terms of past history and current clinical presentation. The patients were matched for age, sex, and level of function. Comorbid patients were most likely to meet criteria for sedative dependence and panic disorder, and had higher scores on the Hamilton Anxiety Scale. In addition, they scored higher on a hypomania scale and had more first-degree relatives with a history of drug abuse.

Relationship of age to TSH response to TRH in depressed men.

The relationship between age and TSH response to TRH was studied in 40 men with unipolar major depressive disorder (range 24-65 years, mean 44.7 years) and 36 healthy male volunteers of similar ages. Both groups were subdivided into younger and older than 40 years of age. "Blunted" TSH response to TRH was observed in 58% of depressed men and in 28% of controls, using a dTSH maximum of less than or equal to 6 microU/ml as a cut-off criterion. Older healthy men had a higher blunting rate (40%) than the younger group (19%). In depressed patients, by contrast, the blunting rate was 50% in the older group and 65% in the younger group. Higher mean maximum dTSH, higher basal TSH and lower mean circulating FT4 levels were also noted in older depressed men, suggestive of a subtle thyroid subsensitivity to TSH stimulation and subclinical primary hypothyroidism that may have contributed to the depression. Age is known to be a confounder of TRH test results. There may be a subset of depressed patients over 40 where the confounding effect of age is associated with an exaggerated, rather than decreased TSH response to TRH.