The Comparative Effectiveness of EEG Biomarkers in Antidepressant Response and Illness Prediction in Major Depressive Disorder

Background: There is growing evidence that individual EEG differences may aid in classifying patients with major depressive disorder (MDD) and also help predict clinical response to antidepressant treatment. This study aims to compare the effectiveness of EEG frequency band power, alpha asymmetry and prefrontal theta cordance towards escitalopram response prediction and MDD diagnosis, in a multi-site initiative. Methods: Resting EEG (eyes open and closed) was recorded from 64 electrodes in 44 depressed patients and 20 healthy controls at baseline, 2 weeks post-treatment and 8 weeks post-treatment. Clinical response was measured as change from baseline MADRS of 50% or more. EEG measures were analyzed (1) at baseline (2) at 2 weeks post-treatment and (3) as an ‘‘early change” variable defined as change in EEG from baseline to 2 weeks post-treatment. Results: At baseline, responders exhibited greater absolute alpha power in the left hemisphere versus the right while non-responders showed the opposite. Responders further exhibited a cortical asymmetry of greater right relative to left activity in parietal areas. Groups also differed in baseline relative delta power with responders showing greater power in the right hemisphere versus the left while non-responders showed the opposite. At 2 weeks post-treatment, responders exhibited greater absolute beta power in the left hemisphere relative to right and the opposite was noted for non-responders. The opposite pattern was noted for absolute and relative delta power at 2 weeks post-treatment. Responders exhibited early reduction in relative alpha power and early increments in relative theta power. Non-responders showed a significant early increase in prefrontal theta cordance. Absolute delta power helped distinguish MDD patients from healthy controls. Conclusions: Hemispheric asymmetries in the alpha and delta bands at pre-treatment baseline and at 2 weeks post-treatment have moderate to moderately strong predictive utility towards antidepressant treatment response. These findings have significant potential for improving clinical practice in psychiatry by eventually guiding clinical choice of treatments. This would greatly benefit patients awaiting relief from depressive symptoms as treatment optimization would help overcome problems associated with delayed recovery. Our results also indicate that resting EEG activity may have clinical utility in predicting MDD diagnosis.

Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95% CI 1.07-1.86, fluoxetine adjOR 1.43 95% CI 0.85-2.40, paroxetine adjOR 1.53, 95% CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95% CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95% CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95% CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95% CI 1.06-5.68), gastroschisis (adjOR 2.42, 95% CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95% CI 1.61-5.61), and clubfoot (adjOR 2.41, 95% CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors.

Education as a Predictor of Antidepressant and Anxiolytic medication use after Bereavement: a population based record linkage study.

Purpose: Educational attainment has been shown to be positively associated with mental health and a potential buffer to stressful events. One stressful life event likely to affect everyone in their lifetime is bereavement. This paper assesses the effect of educational attainment on mental health post bereavement.
Methods: By utilising large administrative datasets, linking Census returns to death records and prescribed medication data, we analysed the bereavement exposure of 208,332 individuals aged 25-74 years. Two-level multi-level logistic regression models were constructed to determine the likelihood of antidepressant medication use (a proxy of mental ill-health) post bereavement given level of educational attainment.
Results: Individuals who are bereaved have greater antidepressant use than those who are not bereaved, with over a quarter (26.5%) of those bereaved by suicide in receipt of antidepressant medication compared to just 12.4% of those not bereaved. Within individuals bereaved by a sudden death those with a University Degree or higher qualifications are 73% less likely to be in receipt of antidepressant medication compared to those with no qualifications, after full adjustment for demographic, socio-economic and area factors (OR=0.27, 95% CI 0.09,0.75). Higher educational attainment and no qualifications have an equivalent effect for those bereaved by suicide.
Conclusions: Education may protect against poor mental health, as measured by the use of antidepressant medication, post bereavement, except in those bereaved by suicide. This is likely due to the improved cognitive, personal and psychological skills gained from time spent in education.

Long-term antidepressant use: patient perspectives of benefits and adverse effects

Long-term antidepressant treatment has increased and there is evidence of adverse effects; however, little is known about patients’ experiences and views of this form of treatment.This study used mixed methods to examine patients’ views and experiences of long-term antidepressant treatment, including benefits and concerns. Data from 180 patients, who were long-term users of antidepressants (3–15 years), were extracted from an anonymous online survey of patients’ experiences of antidepressants in New Zealand. Participants had completed rating scales about the effectiveness of antidepressants, levels of depression before and during antidepressant use, quality of life, and perceived adverse effects. Two open-ended questions allowed participants to comment on personal experiences. The majority (89.4%) reported that antidepressants had improved their depression although 30% reported moderate-to-severe depression on antidepressants. Common adverse effects included withdrawal effects (73.5%), sexual problems (71.8%), and weight gain (65.3%). Adverse emotional effects, such as feeling emotionally numb (64.5%) and addicted (43%), were also common. While the majority of patients were pleased with the benefits of antidepressant treatment, many were concerned about these adverse effects. Some expressed a need for more information about long-term risks and increased information and support to discontinue.

Galanin N-Terminal fragment (1-15) enhances the antidepressant effects of the 5-HT1A receptor agonist 8-OH-DPAT in the Forced Swimming Test.

Galanin and Galanin (1-15) [GAL(1-15)] are implicated in anxiety- and depression related behaviors. Moreover, Galanin modulates 5-HT1A receptor (5-HT1AR) function at autorreceptor and postsynaptic level in the brain. In this study, we have analysed the ability of GAL(1-15) to modulate the effects of the 8-OH-DPAT agonist in the Forced Swimming Test (FST). Groups of rats were assessed in the FST. In the first set of experiments, to evaluate the interactions of 8-OH-DPAT and GAL(1-15), rats received subcutaneously (s.c) the effective doses of 8-OH-DPAT (0.25mg/Kg) 60min before the test and intracerebroventricularly (icv) GAL(1-15)1nmol 15min before the tests alone or in combination. In the second set of experiments, groups of rats received s.c. 8-OH-DPAT (0.125mg/Kg), icv GAL(1-15) 1nmol and icv the GALR2 antagonist M871 3 nmol alone or in combination. The locomotor activity was analysed in the open field test. GAL(1-15) 1nmol enhanced the antidepressant-like effects mediated by the effective dose of the 8-OH-DPAT. GAL(1-15) significantly decreased the immobility (p<0.05) and climbing (p<0.05) and increased the swimming (p<0.01) behaviour induced by an effective dose of 8-OH-DPAT (0.25mg/Kg) in FST. Moreover, after coadministration of GAL(1-15) and threshold dose of 8-OH-DPAT (0.125mg/Kg) a significant decreased appeared in immobility (p<0.01) and climbing (p<0.01) and increased the swimming behavior (p<0.001) vs 8-OH-DPAT group. Moreover, M871 blocked completely this interaction. These results indicate that GAL(1-15) enhances the antidepressant effects induced by 8-OH-DPAT in the FST. These findings may give the basis for the development of novel therapeutic drugs. This study was supported by Junta de Andalucía CVI6476.

Galanin and galanin fragment 1-15 modulate antidepressant responses by targeting 5-HT1AR-GALR heteroreceptor complexes of the ascending midbrain serotonin pathways.

Mood disorders, including depression and anxiety, are among the most prevalent mental illnesses with high socioeconomic impact. Although the underlying mechanisms have not yet been clearly defined in the last decade the importance of the role of neuropeptides, including Galanin (GAL), and/or their receptors in the treatment of stress-related mood disorders is becoming increasingly apparent. GAL is involved in mood regulation, including depression-related and anxiety-like behaviors. Activation of GALR1 and GALR3 receptors results in a depression like behavior while stimulation of GALR2 receptor leads to anti-depressant-like effects. Moreover, GAL modulates 5-HT1A receptors (5-HT1AR), a key receptor in depression at autoreceptor and postsynaptic level in the brain. This interaction can in part be due to the existence of GALR1-5-HT1AR heteroreceptor complexes in discrete brain regions [1]. Not only GAL but also the N-terminal fragments like GAL(1-15) are active in the Central Nervous System [2, 3]. Recently, we described that GAL(1-15) induces strong depression-related and anxiogenic-like effects in rats, and these effects were significantly stronger than the ones induced by GAL [4]. The GALR1-GALR2 heteroreceptor complexes in the dorsal hippocampus and especially in the dorsal raphe (DR), areas rich in GAL(1-15) binding sites [5] were involved in these effects [4, 6] and demonstrated also in cellular models. In the present study, we have analyzed the ability of GAL(1-15) to modulate 5-HT1AR located at postjunctional sites and at the soma-dendritic level in rats. We have analyzed the effect of GAL(1-15) on the 5-HT1AR-mediated response in a behavioral test of depression and the involvement of the GALR2 in these effects. GAL(1-15) enhanced the antidepressant effects induced by the 5-HT1AR agonist 8-OH-DPAT in the forced swimming test [7]. These effects were stronger than the ones induced by GAL. The mechanism of this action involved interactions at the receptor level in the plasma membrane with changes also at the transcriptional level. Thus, GAL(1-15) affected the binding characteristics as well as the mRNA level of 5-HT1AR in the dorsal hippocampus and DR. GALR2 was involved in these effects, since the specific GALR2 antagonist M871 blocked GAL(1-15) mediated actions at the behavioral and receptor level [7]. Furthermore, the results on the proximity ligation assay (PLA) in this work suggest the existence of GALR1-GALR2-5-HT1AR heteroreceptor complexes since positive PLA were obtained for both GALR1-5-HT1AR and GALR2-5-HT1AR complexes in the DR and hippocampus. Moreover the studies on RN33B cells, where GALR1, GALR2 and 5-HT1AR exist [4], also showed PLA-positive clusters indicating the existence of GALR1-5-HT1AR and GALR2-5-HT1AR complexes in these cells [7]. In conclusion, our results indicate that GAL(1–15) enhances the antidepressant effects induced by the 5-HT1AR agonist 8-OH-DPAT probably acting on GALR1-GALR2-5-HT1AR heteroreceptor located at postjunctional sites and at the soma-dendritic level. The development of new drugs specifically targeting these heteroreceptor complexes may offer a novel strategy for treatment of depression. This work has been supported by Junta de Andalucia CVI646 1. Borroto-Escuela, D.O., et al., Galanin receptor-1 modulates 5-hydroxtryptamine-1A signaling via heterodimerization. Biochem Biophys Res Commun, 2010. 393(4): p. 767-72. 2. Hedlund, P.B. and K. Fuxe, Galanin and 5-HT1A receptor interactions as an integrative mechanism in 5-HT neurotransmission in the brain. Ann N Y Acad Sci, 1996. 780: p. 193-212. 3. Diaz-Cabiale, Z., et al., Neurochemical modulation of central cardiovascular control: the integrative role of galanin. EXS, 2010. 102: p. 113-31. 4. Millon, C., et al., A role for galanin N-terminal fragment (1-15) in anxiety- and depression-related behaviors in rats. Int J Neuropsychopharmacol, 2015. 18(3). 5. Hedlund, P.B., N. Yanaihara, and K. Fuxe, Evidence for specific N-terminal galanin fragment binding sites in the rat brain. Eur J Pharmacol, 1992. 224(2-3): p. 203-5. 6. Borroto-Escuela, D.O., et al., Preferential activation by galanin 1-15 fragment of the GalR1 protomer of a GalR1-GalR2 heteroreceptor complex. Biochem Biophys Res Commun, 2014. 452(3): p. 347-53. 7. Millon, C., et al., Galanin (1-15) enhances the antidepressant effects of the 5-HT1A receptor agonist 8-OH-DPAT: involvement of the raphe-hippocampal 5-HT neuron system. Brain Struct Funct, 2016.

The Comparative Effectiveness of EEG Biomarkers in Antidepressant Response and Illness Prediction in Major Depressive Disorder

Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2016-08-27 00:55:35.782

Antidepressant effects of exercise: a role for the adiponectin-PGC-1α-kynurenine triad?

It is well-recognized that exercise improves mental health, e.g., by decreasing depressive behaviors, improving hippocampal-dependent learning and neurogenesis, and increasing dendritic plasticity. Yet how exercise influences the brain at the molecular level is not clearly understood. Yau et al recently reported that the antidepressant effects of physical exercise are mainly mediated by adiponectin, an adipocyte-secreted hormone ('adipocytokine') with neuroprotective effects at the central nervous system level (Yau et al., 2014). This article is protected by copyright. All rights reserved

A Highly Improved Method For Sensitive Determination Of Amitriptyline In Pharmaceutical Formulations Using An Unmodified Carbon Nanotube Electrode In The Presence Of Sulfuric Acid.

The present paper describes a novel, simple and reliable differential pulse voltammetric method for determining amitriptyline (AMT) in pharmaceutical formulations. It has been described for many authors that this antidepressant is electrochemically inactive at carbon electrodes. However, the procedure proposed herein consisted in electrochemically oxidizing AMT at an unmodified carbon nanotube paste electrode in the presence of 0.1 mol L(-1) sulfuric acid used as electrolyte. At such concentration, the acid facilitated the AMT electroxidation through one-electron transfer at 1.33 V vs. Ag/AgCl, as observed by the augmentation of peak current. Concerning optimized conditions (modulation time 5 ms, scan rate 90 mV s(-1), and pulse amplitude 120 mV) a linear calibration curve was constructed in the range of 0.0-30.0 μmol L(-1), with a correlation coefficient of 0.9991 and a limit of detection of 1.61 μmol L(-1). The procedure was successfully validated for intra- and inter-day precision and accuracy. Moreover, its feasibility was assessed through analysis of commercial pharmaceutical formulations and it has been compared to the UV-vis spectrophotometric method used as standard analytical technique recommended by the Brazilian Pharmacopoeia.

5-HT1A autoreceptor modulation of locomotor activity induced by nitric oxide in the rat dorsal raphe nucleus

The dorsal raphe nucleus (DRN) is the origin of ascending serotonergic projections and is considered to be an important component of the brain circuit that mediates anxiety- and depression-related behaviors. A large fraction of DRN serotonin-positive neurons contain nitric oxide (NO). Disruption of NO-mediated neurotransmission in the DRN by NO synthase inhibitors produces anxiolytic- and antidepressant-like effects in rats and also induces nonspecific interference with locomotor activity. We investigated the involvement of the 5-HT1A autoreceptor in the locomotor effects induced by NO in the DRN of male Wistar rats (280-310 g, N = 9-10 per group). The NO donor 3-morpholinosylnomine hydrochloride (SIN-1, 150, and 300 nmol) and the NO scavenger S-3-carboxy-4-hydroxyphenylglycine (carboxy-PTIO, 0.1-3.0 nmol) were injected into the DRN of rats immediately before they were exposed to the open field for 10 min. To evaluate the involvement of the 5-HT1A receptor and the N-methyl-D-aspartate (NMDA) glutamate receptor in the locomotor effects of NO, animals were pretreated with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 8 nmol), the 5-HT1A receptor antagonist N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY-100635, 0.37 nmol), and the NMDA receptor antagonist DL-2-amino-7-phosphonoheptanoic acid (AP7, 1 nmol), followed by microinjection of SIN-1 into the DRN. SIN-1 increased the distance traveled (mean ± SEM) in the open-field test (4431 ± 306.1 cm; F7,63 = 2.44, P = 0.028) and this effect was blocked by previous 8-OH-DPAT (2885 ± 490.4 cm) or AP7 (3335 ± 283.5 cm) administration (P < 0.05, Duncan test). These results indicate that 5-HT1A receptor activation and/or facilitation of glutamate neurotransmission can modulate the locomotor effects induced by NO in the DRN.

Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting

The use of neuromodulation as a treatment for major depressive disorder (MDD) has recently attracted renewed interest due to development of other non-pharmacological therapies besides electroconvulsive therapy (ECT) such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). METHOD: We convened a working group of researchers to discuss the updates and key challenges of neuromodulation use for the treatment of MDD. RESULTS: The state-of-art of neuromodulation techniques was reviewed and discussed in four sections: [1] epidemiology and pathophysiology of MDD; [2] a comprehensive overview of the neuromodulation techniques; [3] using neuromodulation techniques in MDD associated with non-psychiatric conditions; [4] the main challenges of neuromodulation research and alternatives to overcome them. DISCUSSION: ECT is the first-line treatment for severe depression. TMS and tDCS are strategies with a relative benign profile of side effects; however, while TMS effects are comparable to antidepressant drugs for treating MDD; further research is needed to establish the role of tDCS. DBS and VNS are invasive strategies with a possible role in treatment-resistant depression. In summary, MDD is a chronic and incapacitating condition with a high prevalence; therefore clinicians should consider all the treatment options including invasive and non-invasive neuromodulation approaches.

Depressão, antidepressivos e sistema imune: um novo olhar sobre um velho problema

CONTEXTO: A hipótese monoaminérgica da depressão não responde a uma série de questões, tais como "quais as causas dos distúrbios monoaminérgicos?" e "como explicar uma taxa de 30% de refratariedade aos antidepressivos?". Sendo assim, outras teorias têm sido propostas, entre elas, aquelas que enfocam as participações dos sistemas imune e endócrino. OBJETIVOS: Analisar criticamente o papel do sistema de resposta imunoinflamatória na depressão e discutir a interação dos antidepressivos com esse sistema, tanto do ponto de vista básico como clínico. MÉTODOS: Realizou-se pesquisa bibliográfica utilizando-se as bases de dados MedLine e SciELO. RESULTADOS: Pacientes vítimas de estresse crônico e depressão apresentam ativação das respostas imunoinflamatórias e do eixo hipotálamo-hipófise-adrenal, os quais, direta ou indiretamente, influenciam a neurotransmissão. Nesse sentido, a utilização de antidepressivos não apenas aumenta a disponibilidade de neurotransmissores na fenda sináptica, mas também induz mudança do padrão de resposta imune Th1 - pró-inflamatório - para o Th2, que é antiinflamatório. Além disso, sabe-se que pacientes não responsivos aos antidepressivos possuem o sistema imuneinflamatório mais ativo. No entanto, há uma série de dados controversos na literatura, havendo indícios de um perfil imune diferente de acordo com o tipo de depressão. CONCLUSÕES: A compreensão de aspectos neuroimunes presentes na depressão poderia contribuir para um melhor entendimento das bases biológicas desse transtorno e, possivelmente, para novas perspectivas na busca de uma terapêutica mais efetiva.

Harmine and imipramine promote antioxidant activities in prefrontal cortex and hippocampus

A growing body of evidence has suggested that reactive oxygen species (ROS) may play an important role in the physiopathology of depression. Evidence has pointed to the beta-carboline harmine as a potential therapeutic target for the treatment of depression. The present study we evaluated the effects of acute and chronic administration of harmine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) or saline in lipid and protein oxidation levels and superoxide dismutase (SOD) and catalase (CAT) activities in rat prefrontal cortex and hippocampus. Acute and chronic treatments with imipramine and harmine reduced lipid and protein oxidation, compared to control group in prefrontal cortex and hippocampus. The SOD and CAT activities increased with acute and chronic treatments with imipramine and harmine, compared to control group in prefrontal cortex and hippocampus. In conclusion, our results indicate positive effects of imipramine antidepressant and beta-carboline harmine of oxidative stress parameters, increasing SOD and CAT activities and decreasing lipid and protein oxidation.

Placebo Response of Non-Pharmacological and Pharmacological Trials in Major Depression: A Systematic Review and Meta-Analysis

Background: Although meta-analyses have shown that placebo responses are large in Major Depressive Disorder (MDD) trials; the placebo response of devices such as repetitive transcranial magnetic stimulation (rTMS) has not been systematically assessed. We proposed to assess placebo responses in two categories of MDD trials: pharmacological (antidepressant drugs) and non-pharmacological (device-rTMS) trials. Methodology/Principal Findings: We performed a systematic review and meta-analysis of the literature from April 2002 to April 2008, searching MEDLINE, Cochrane, Scielo and CRISP electronic databases and reference lists from retrieved studies and conference abstracts. We used the keywords placebo and depression and escitalopram for pharmacological studies; and transcranial magnetic stimulation and depression and sham for non-pharmacological studies. All randomized, double-blinded, placebo-controlled, parallel articles on major depressive disorder were included. Forty-one studies met our inclusion criteria-29 in the rTMS arm and 12 in the escitalopram arm. We extracted the mean and standard values of depression scores in the placebo group of each study. Then, we calculated the pooled effect size for escitalopram and rTMS arm separately, using Cohen's d as the measure of effect size. We found that placebo response are large for both escitalopram (Cohen's d-random-effects model-1.48; 95% C.I. 1.26 to 1.6) and rTMS studies (0.82; 95% C.I. 0.63 to 1). Exploratory analyses show that sham response is associated with refractoriness and with the use of rTMS as an add-on therapy, but not with age, gender and sham method utilized. Conclusions/Significance: We confirmed that placebo response in MDD is large regardless of the intervention and is associated with depression refractoriness and treatment combination (add-on rTMS studies). The magnitude of the placebo response seems to be related with study population and study design rather than the intervention itself.