losartan-potassium and Mood-Disorders

Mood disorders are associated with significant psychosocial and occupational disability. It is estimated that major depressive disorder (MDD) will become the second leading cause of disability worldwide by 2020. Existing pharmacological and psychological treatments are limited for targeting cognitive dysfunctions in mood disorders. However, growing evidence from human and animal studies has shown that treatment with erythropoietin (EPO) can improve cognitive function. A recent study involving EPO-treated patients with mood disorders showed that the neural basis for their cognitive improvements appeared to involve an increase in hippocampal volume. Molecular mechanisms underlying hippocampal changes have been proposed, including the activation of anti-apoptotic, antioxidant, pro-survival and anti-inflammatory signalling pathways. The aim of this review is to describe the potential importance of glycogen synthase kinase 3-beta (GSK3β) as a multi-potent molecular mechanism of EPO-induced hippocampal volume change in mood disorder patients. We first examine published associations between EPO administration, mood disorders, cognition and hippocampal volume. We then highlight evidence suggesting that GSK3β influences hippocampal volume in MDD patients, and how this could assist with targeting more precise treatments particularly for cognitive deficits in patients with mood disorders. We conclude by suggesting how this developing area of research can be further advanced, such as using pharmacogenetic studies of EPO treatment in patients with mood disorders.

Topics: Animals; Cognition; Erythropoietin; Glycogen Synthase Kinase 3 beta; Hippocampus; Humans; Mood Disorders; Neuroprotective Agents

Cognitive dysfunction is a core feature in a range of neuropsychiatric disorders which reduces patients' workforce capacity - the largest socio-economic cost of these disorders. Nevertheless, there is no clinically available medical treatment with robust and enduring efficacy on cognitive deficits in most neuropsychiatric conditions. Recent research has shown that erythropoietin may have beneficial effects on cognitive dysfunction across neuropsychiatric disorders, including bipolar and unipolar disorders, schizophrenia, Parkinson's disease and multiple sclerosis.

Topics: Bipolar Disorder; Cognition; Cognitive Dysfunction; Erythropoietin; Humans; Mood Disorders; Multiple Sclerosis; Parkinson Disease; Schizophrenia

Current pharmacological treatments for depression have a significant treatment-onset-response delay, an insufficient efficacy for many patients and fail to reverse cognitive dysfunction. Erythropoietin (EPO) has neuroprotective and neurotrophic actions and improves cognitive function in animal models of acute and chronic neurodegenerative conditions and in patients with cognitive decline.. We systematically reviewed the published findings from animal and human studies exploring the potential of EPO to treat depression-related cognitive dysfunction and depression.. We identified five animal studies (two in male rats, two in male mice and one in male rats and mice) and seven human proof-of-concept studies (five in healthy volunteers and two in depressed patients) that investigated the above. All of the reviewed animal studies but one and all human studies demonstrated beneficial effects of EPO on hippocampus-dependent memory and antidepressant-like effects. These effects appear to be mediated through direct neurobiological actions of EPO rather than upregulation of red cell mass.. The reviewed studies demonstrate beneficial effects of EPO on hippocampus-dependent memory function and on depression-relevant behavior, thus highlighting EPO as a candidate agent for future management of cognitive dysfunction and mood symptoms in depression. Larger-scale clinical trials of EPO as a treatment for mood and neurocognitive symptoms in patients with mood disorder are therefore warranted.

Topics: Affect; Animals; Controlled Clinical Trials as Topic; Depression; Erythropoietin; Humans; Memory Disorders; Mood Disorders

Several recently published studies describe moderate to severe cognitive dysfunction in breast cancer survivors who were treated with adjuvant chemotherapy 1-5 years before undergoing extensive neuropsychological testing. While these studies are hypothesis-generating and preliminary given their small size and retrospective nature, they consistently suggest that between approximately 15% and 25% of chemotherapy-treated breast cancer patients will have evidence of cognitive dysfunction some years after chemotherapy, compared to about 10% of breast cancer survivors who did not receive chemotherapy. Recent preclinical data strongly suggest that erythropoetin is a potent, endogenous neuroprotective agent that prevents neuronal apoptosis from a variety of insults including hypoxia, trauma, subarachnoidal hemorrhage, and encephalitis. Erythropoietin also appears to enhance learning in a mouse spatial learning maze model. We have conducted a pilot study of epoetin alfa versus placebo in early-stage breast cancer patients who received standard adjuvant anthracycline-based chemotherapy to determine the feasibility of administering standardized neurocognitive assessment tests in the oncology practice setting in order to understand whether the Executive Interview 25 test can detect the subtle cognitive impairment in verbal fluency, attention, and short-term memory observed with chemotherapy, and to assess whether epoetin alfa-treated patients have less evidence of cognitive dysfunction during and 6 months after chemotherapy compared with control-treated patients. We report here the preliminary results of this pilot clinical trial.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Breast Neoplasms; Chemotherapy, Adjuvant; Cognition Disorders; Controlled Clinical Trials as Topic; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Humans; Mastectomy; Mice; Mood Disorders; Patient Satisfaction; Pilot Projects; Prognosis; Quality of Life; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Bipolar disorder (BD) and unipolar disorder (UD) are associated with cognitive deficits and abnormal neural activity in a "cognitive control network." There is an increased prevalence of cognitive dysfunction in psychiatric patients' first-degree relatives, which constitutes a risk factor for psychiatric illness onset. However, there is no treatment with enduring pro-cognitive efficacy. We found preliminary evidence for beneficial effects of eight weekly doses of recombinant human erythropoietin (EPO) on cognition in BD in a recent randomized controlled trial (RCT). The present RCT consists of two sub-studies that extend our previous work by investigating important novel aspects: (1) the effects of 12 weekly doses of EPO on cognition in first-degree relatives of patients with BD, UD, or schizophrenia; and (2) the effects of extending the treatment schedule from 8 to 12 weeks in remitted patients with BD or UD; and (3) assessment of early treatment-associated neural activity changes that may predict cognitive improvement.. The trial comprises two parallel sub-studies with randomized, controlled, double-blinded, parallel group designs. First-degree relatives (sub-study 1; n = 52) and partially or fully remitted patients with BD or UD (sub-study 2; n = 52) with objectively verified cognitive dysfunction are randomized to receive weekly high-dose EPO (40,000 IU/mL) or placebo (saline) infusions for 12 weeks. Assessments of cognition and mood are conducted at baseline, after two weeks of treatment, after treatment completion, and at six-month follow-up. Functional magnetic resonance imaging (fMRI) is conducted at baseline and after two weeks of treatment. Psychosocial function is assessed at baseline, after treatment completion and six-month follow-up. The primary outcome is change in a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference by including 52 first-degree relatives and 52 patients with BD or UD, respectively. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data are analyzed with the FMRIB Software Library.. If this trial reveals pro-cognitive effects of EPO, this may influence future treatment of mood disorders and/or preventive strategies in at-risk populations. The fMRI analyses may unravel key neurobiological targets for pro-cognitive treatment.. ClinicalTrials.gov , NCT03315897. Registered on 20 October 2017.

Topics: Adolescent; Adult; Aged; Bipolar Disorder; Cognition; Depressive Disorder; Double-Blind Method; Erythropoietin; Executive Function; Family; Humans; Magnetic Resonance Imaging; Middle Aged; Mood Disorders; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Recombinant Proteins; Research Design; Sample Size; Young Adult

There is no established efficacious treatment for cognitive dysfunction in unipolar and bipolar disorder. This may be partially due to lack of consensus regarding the need to screen for cognitive impairment in cognition trials or which screening criteria to use. We have demonstrated in 2 randomized placebo-controlled trials that 8 weeks of erythropoietin (EPO) treatment has beneficial effects on verbal memory across unipolar and bipolar disorder, with 58% of EPO-treated patients displaying a clinically relevant memory improvement as compared to 15% of those treated with placebo.. We reassessed the data from our 2 EPO trials conducted between September 2009 and October 2012 to determine whether objective performance-based memory impairment or subjective self-rated cognitive impairment at baseline was related to the effect of EPO on cognitive function as assessed by Rey Auditory Verbal Learning Test (RAVLT) total recall with multiple logistic regression adjusted for diagnosis, age, gender, symptom severity, and education levels.. We included 79 patients with an ICD-10 diagnosis of unipolar or bipolar disorder, of whom 39 received EPO and 40 received placebo (saline). For EPO-treated patients with objective memory dysfunction at baseline (n = 16) (defined as RAVLT total recall ≤ 43), the odds of a clinically relevant memory improvement were increased by a factor of 290.6 (95% CI, 2.7-31,316.4; P = .02) compared to patients with no baseline impairment (n = 23). Subjective cognitive complaints (measured with the Cognitive and Physical Functioning Questionnaire) and longer illness duration were associated with small increases in patients' chances of treatment efficacy on memory (53% and 16% increase, respectively; P ≤ .04). Diagnosis, gender, age, baseline depression severity, and number of mood episodes did not significantly change the chances of EPO treatment success (P ≥ .06). In the placebo-treated group, the odds of memory improvement were not significantly different for patients with or without objectively defined memory dysfunction (P ≥ .59) or subjective complaints at baseline (P ≥ .06).. Baseline objectively assessed memory impairments and-to a lesser degree-subjective cognitive complaints increased the chances of treatment efficacy on cognition in unipolar and bipolar disorder.. ClinicalTrials.gov identifier: NCT00916552.

Topics: Adult; Aged; Bipolar Disorder; Cognitive Dysfunction; Erythropoietin; Female; Humans; Male; Memory Disorders; Middle Aged; Mood Disorders; Outcome Assessment, Health Care; Young Adult

Persistent cognitive dysfunction in depression and bipolar disorder (BD) impedes patients' functional recovery. Erythropoietin (EPO) increases neuroplasticity and reduces cognitive difficulties in treatment-resistant depression (TRD) and remitted BD. This magnetic resonance imaging study assessed the neuroanatomical basis for these effects.. Patients with TRD who were moderately depressed or BD in partial remission were randomized to 8 weekly EPO (40,000 IU) or saline infusions in a double-blind, parallel-group design. Patients underwent magnetic resonance imaging, memory assessment with the Rey Auditory Verbal Learning Test, and mood ratings with the Beck Depression Inventory, Hamilton Depression Rating Scale, and Young Mania Rating Scale at baseline and week 14. Hippocampus segmentation and analysis of hippocampal volume, shape, and gray matter density were conducted with FMRIB Software Library tools. Memory change was analyzed with repeated-measures analysis of covariance adjusted for depression symptoms, diagnosis, age, and gender.. Eighty-four patients were randomized; 1 patient withdrew and data collection was incomplete for 14 patients; data were thus analyzed for 69 patients (EPO: n = 35, saline: n = 34). Compared with saline, EPO was associated with mood-independent memory improvement and reversal of brain matter loss in the left hippocampal cornu ammonis 1 to cornu ammonis 3 and subiculum. Using the entire sample, memory improvement was associated with subfield hippocampal volume increase independent of mood change.. EPO-associated memory improvement in TRD and BD may be mediated by reversal of brain matter loss in a subfield of the left hippocampus. EPO may provide a therapeutic option for patients with mood disorders who have impaired neuroplasticity and cognition.

Topics: Adult; Bipolar Disorder; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Erythropoietin; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Memory; Middle Aged; Mood Disorders; Psychiatric Status Rating Scales

The study aims to investigate the effect of repeated infusions of recombinant erythropoietin (EPO) on plasma brain derived neurotrophic factor (BDNF) levels in patients with affective disorders. In total, 83 patients were recruited: 40 currently depressed patients with treatment-resistant depression (TRD) (Hamilton Depression Rating Scale-17 items (HDRS-17) score >17) (study 1) and 43 patients with bipolar disorder (BD) in partial remission (HDRS-17 and Young Mania Rating Scale (YMRS) ≤ 14) (study 2). In both studies, patients were randomised to receive eight weekly EPO (Eprex; 40,000 IU) or saline (0.9% NaCl) infusions in a double-blind, placebo-controlled, parallel--group design. Plasma BDNF levels were measured at baseline and at weeks 5, 9 and at follow up, week 14. In contrast with our hypothesis, EPO down regulated plasma BDNF levels in patients with TRD (mean reduction at week 9 (95% CI): EPO 10.94 ng/l (4.51-21.41 ng/l); mean increase at week 9: Saline 0.52 ng/l, p=0.04 (-5.88-4.48 ng/l) p=0.04, partial ŋ2=0.12). No significant effects were found on BDNF levels in partially remitted patients with BD (p=0.35). The present effects of EPO on BDNF levels in patients with TRD point to a role of neurotrophic factors in the potential effects of EPO seen in TRD and BD. The neurobiological mechanisms underlying these effects and the interaction between EPO and peripheral levels on BDNF need to be further elucidated in human studies including a broad range of biomarkers.. ClinicalTrials.gov: NCT00916552.

Topics: Adult; Brain-Derived Neurotrophic Factor; Depressive Disorder, Treatment-Resistant; Erythropoietin; Female; Humans; Male; Mood Disorders; Recombinant Proteins; Remission Induction

Several recently published studies describe moderate to severe cognitive dysfunction in breast cancer survivors who were treated with adjuvant chemotherapy 1-5 years before undergoing extensive neuropsychological testing. While these studies are hypothesis-generating and preliminary given their small size and retrospective nature, they consistently suggest that between approximately 15% and 25% of chemotherapy-treated breast cancer patients will have evidence of cognitive dysfunction some years after chemotherapy, compared to about 10% of breast cancer survivors who did not receive chemotherapy. Recent preclinical data strongly suggest that erythropoetin is a potent, endogenous neuroprotective agent that prevents neuronal apoptosis from a variety of insults including hypoxia, trauma, subarachnoidal hemorrhage, and encephalitis. Erythropoietin also appears to enhance learning in a mouse spatial learning maze model. We have conducted a pilot study of epoetin alfa versus placebo in early-stage breast cancer patients who received standard adjuvant anthracycline-based chemotherapy to determine the feasibility of administering standardized neurocognitive assessment tests in the oncology practice setting in order to understand whether the Executive Interview 25 test can detect the subtle cognitive impairment in verbal fluency, attention, and short-term memory observed with chemotherapy, and to assess whether epoetin alfa-treated patients have less evidence of cognitive dysfunction during and 6 months after chemotherapy compared with control-treated patients. We report here the preliminary results of this pilot clinical trial.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Breast Neoplasms; Chemotherapy, Adjuvant; Cognition Disorders; Controlled Clinical Trials as Topic; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Humans; Mastectomy; Mice; Mood Disorders; Patient Satisfaction; Pilot Projects; Prognosis; Quality of Life; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Topics: Bipolar Disorder; Erythropoietin; Humans; Mood Disorders; Recombinant Proteins

Topics: Bipolar Disorder; Erythropoietin; Female; Hippocampus; Humans; Male; Memory; Mood Disorders