Depression, antidepressants, and peripheral blood components

Department of Psychiatry, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
Neuro endocrinology letters (Impact Factor: 0.8). 03/2008; 29(1):17-28.
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The biological attributes of affective disorders and factors which are able to predict a response to treatment with antidepressants have not been identified sufficiently. A number of biochemical variables in peripheral blood constituents have been tested for this purpose, as a consequence of the lack of availability of human brain tissue. At first, the biological attributes of mental disorders were sought at the level of concentrations of neurotransmitters and their metabolites or precursors. Later on, attention shifted to receptor systems. Since the 1990s, intracellular processes influenced by an illness or its treatment with psychopharmaceuticals have been at the forefront of interest. Interest in biological predictors of treatment with antidepressants has reappeared in recent years, thanks to new laboratory techniques which make it possible to monitor cellular processes associated with the transmission of nerve signals in the brain. These processes can also be studied in plasma and blood elements, especially lymphocytes and platelets. The selection of the qualities to which attention is paid can be derived from today's most widely discussed biochemical hypotheses of affective disorders, especially the monoamine hypothesis and the molecular and cellular theory of depression. Mitochondrial enzymes can also play an important role in the pathophysiology of depression and the effects of antidepressants. In this paper, we sum up the cellular, neurochemical, neuroendocrine, genetic, and neuroimmunological qualities which can be measured in peripheral blood and which appear to be indicators of affective disorders, or parameters which make it possible to predict therapeutic responses to antidepressant administration.

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Available from: Zdenek Fisar, Oct 04, 2015
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    • "Blood-based biomarkers have been investigated extensively for both depressive disorder (Fišar and Raboch, 2008) and AD (Doecke et al., 2012). Plasma, platelets and peripheral blood mononuclear cells are the key components of peripheral blood in studies of pathophysiology of neuropsychiatric diseases, such as mood disorders and AD (Maes et al., 2009). "
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    ABSTRACT: Glycogen synthase kinase-3β (GSK3β), cAMP-response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) play critical roles in neuronal survival, synaptic plasticity and memory and participate in the pathophysiology of both depressive disorder and Alzheimer's disease (AD). This study was designed to determine the association of GSK3β activity, CREB activity and BDNF concentration in peripheral blood of patients with AD with or without depressive symptoms and in depressive patients without AD. GSK3β activity in platelets, CREB activity in lymphocytes and BDNF concentration in plasma, platelet-rich plasma or platelets were measured in 85AD patients (36 of whom displayed co-morbid depressive symptoms), 65 non-AD patients with depressive disorder and 96 healthy controls. AD patients were clinically assessed for stage of dementia, cognitive impairment and severity of depressive symptoms. Depressive patients were clinically assessed for severity of depression. We observed increased CREB and GSK3β activity in AD with depressive symptoms or in AD at mild stage of dementia. Decreased BDNF concentration was found in platelet-rich plasma of AD patients at moderate to severe stages of dementia or in AD without depressive symptoms. An association was revealed of the severity of cognitive impairment with the increase of GSK3β in the platelets of AD patients with mild dementia. In depressive patients, a lower concentration of phosphorylated GSK3β was associated with a higher severity of depression. Association was confirmed between severity of depression, CREB activation, and BDNF concentration in drug-naïve depressive patients. Our data demonstrated that AD is accompanied by increased CREB activity in lymphocytes and a decreased concentration of BDNF in platelet-rich plasma. The decreased BDNF concentration appears to correlate with moderate to severe stages of dementia in AD. Observation of decreased phosphorylation of GSK3β in platelets of both AD patients with depressive symptoms and depressive patients after treatment confirms the role of increased GSK3β activity in the pathophysiology of both AD and depressive disorder. Associations were confirmed between AD and platelet GSK3β activity, lymphocyte CREB activity and plasma BDNF. CREB activity and platelet BDNF concentration seems to be related to depressive disorder.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 12/2013; 50. DOI:10.1016/j.pnpbp.2013.12.001 · 3.69 Impact Factor
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    • "It is supposed that MAO-B inhibition may slow the course of various neurodegenerative disorders; so, selective inhibitors of MAO-B may be efficacious in treating of Parkinson's disease (Horstink et al. 2006) and possibly Alzheimer's disease (Riederer et al. 2004). MAO-B is the sole type in human platelets and the amino acid sequences of MAO-B in both platelets and brain are identical (Chen et al. 1993); so, platelet MAO can be adopted as a useful surrogate model for the study of aspects of central neuronal function related to monoaminergic neurotransmission (Fišar & Raboch 2008). "
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    ABSTRACT: OBJECTIVE: Monoamine oxidase (MAO), the enzyme responsible for metabolism of monoamine neurotransmitters, has an important role in the brain development and function, and MAO inhibitors have a range of potential therapeutic uses. We investigated systematically in vitro effects of pharmacologically different antidepressants and mood stabilizers on MAO activity. Methods: Effects of drugs on the activity of MAO were measured in crude mitochondrial fraction isolated from cortex of pig brain, when radiolabeled serotonin (for MAO-A) or phenylethylamine (for MAO-B) was used as substrate. The several antidepressants and mood stabilizers were compared with effects of well known MAO inhibitors such as moclobemide, iproniazid, pargyline, and clorgyline. Results: In general, the effect of tested drugs was found to be inhibitory. The half maximal inhibitory concentration, parameters of enzyme kinetic, and mechanism of inhibition were determined. MAO-A was inhibited by the following drugs: pargyline > clorgyline > iproniazid > fluoxetine > desipramine > amitriptyline > imipramine > citalopram > venlafaxine > reboxetine > olanzapine > mirtazapine > tianeptine > moclobemide, cocaine > lithium, valproate. MAO-B was inhibited by the following drugs: pargyline > clorgyline > iproniazid > fluoxetine > venlafaxine > amitriptyline > olanzapine > citalopram > desipramine > reboxetine > imipramine > tianeptine > mirtazapine, cocaine > moclobemide, lithium, valproate. The mechanism of inhibition of MAOs by several antidepressants was found various. Conclusions: It was concluded that MAO activity is acutely affected by pharmacologically different antidepressants at relatively high drug concentrations; this effect is inhibitory. There are differences both in inhibitory potency and in mechanism of inhibition between both several drugs and the two MAO isoforms. While MAO inhibition is not primary biochemical effect related to their therapeutic action, it can be supposed that decrease of MAO activity may be concerned in some effects of these drugs on serotonergic, noradrenergic, and dopaminergic neurotransmission.
    Neuro endocrinology letters 01/2010; 31(5):645-56. · 0.80 Impact Factor
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    ABSTRACT: Bipolar disorder is a debilitating psychiatric illness presenting with recurrent mania and depression. The pathophysiology of bipolar disorder is poorly understood, and molecular targets in the treatment of bipolar disorder remain to be identified. Preclinical studies have suggested that glycogen synthase kinase-3 (GSK3) is a potential therapeutic target in bipolar disorder, but evidence of abnormal GSK3 in human bipolar disorder and its response to treatment is still lacking. This study was conducted in acutely ill type I bipolar disorder subjects who were hospitalized for a manic episode. The protein level and the inhibitory serine phosphorylation of GSK3 in peripheral blood mononuclear cells of bipolar manic and healthy control subjects were compared, and the response of GSK3 to antimanic treatment was evaluated. The levels of GSK3α and GSK3β in this group of bipolar manic subjects were higher than healthy controls. Symptom improvement during an eight-week antimanic treatment with lithium, valproate, and atypical antipsychotics was accompanied by a significant increase in the inhibitory serine phosphorylation of GSK3, but not the total level of GSK3, whereas concomitant electroconvulsive therapy treatment during a manic episode appeared to dampen the response of GSK3 to pharmacological treatment. Results of this study suggest that GSK3 can be modified during the treatment of bipolar mania. This finding in human bipolar disorder is in agreement with preclinical data suggesting that inhibition of GSK3 by increasing serine phosphorylation is a response of GSK3 to psychotropics used in bipolar disorder, supporting the notion that GSK3 is a promising molecular target in the pharmacological treatment of bipolar disorder.
    Bipolar Disorders 11/2010; 12(7):741-52. DOI:10.1111/j.1399-5618.2010.00866.x · 4.97 Impact Factor
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