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Acta Psychiatr Scand 2015: 131: 397–400 All rights reserved
ACTA PSYCHIATRICA SCANDINAVICA
Debate section Letters to the editor
Considerations on mental disorders: a neurophysiological approach DOI: 10.1111/acps.12409 It is interesting that anti-epileptica which are sodium channel blockers, for example valproate, have an effect both on epilepsy and on bipolar disorder (1). A sodium channel blocker decreases the permeability of membranes for sodium indicating that the two diseases are membrane diseases due to an increase in permeability of the membranes to sodium. The effect is selective. If it affects the sensory nerves, the disease is the bipolar manicdepressive disorder. If it affects the motoric nerves, it is epilepsy. An increase of nerve membranes permeability to sodium gives a decrease of the nerve membrane potential. At a low decrease, it becomes easier to trigger a nerve impulse, which means an increase in nerve irritability, which may explain a manic disorder. At a further decrease of the membrane potential, the nerve system irritability is decreased, which may explain a depressive disorder. The bipolar depressive disorder reacts to drugs which decreases the permeability to sodium, while the unipolar does not (2). Could it be that the unipolar depression also is due to a decreased membrane potential, but not due to an increase of nerve membranes to sodium, but to a decrease of permeability to potassium which also will give a decreased membrane potential?
DOI: 10.1111/acps.12410 Reply We read with interest Doctor Skou’s ‘Letter to Editor’ discussing the possibility that epilepsy and bipolar disorder are membrane diseases, based on his observations that attest to the efficacy of valproate to treat both diseases: Valproate blocks sodium channels leading to altered membrane potential (1). We note that epilepsy (2) and bipolar disorder (3) also manifest changes to mitochondrial function and consequently alterations to the redox state of proteins. These findings support Doctor Skou’s postulation of a common pathophysiology, albeit with different levels of system activation which in turn results in different clinical manifestations. In fact, it is expected that mania is associated with high levels of energy, or oxidative stress, whereas the opposite is expected for depression. Maintenance of proper mitochondrial function is essential for neuronal homeostasis and proper release of neurotransmitters (4). During oxidative phosphorylation, reactive
A test would be if potassium channel activators have an effect on the disease. A decrease of membrane potential can also be due to a combined effect of an increase in permeability to sodium and decrease of permeability to potassium. Could this give the very complex mental disorder schizophrenia? A test would be if a treatment with a sodium channel blocker plus a potassium channel activator has an effect on the disease. J. C. Skou University of Aarhus, Aarhus, Denmark E-mail: [email protected]
References 1. Ogungbenro K, Aarons L; CRESim & Epi-CRESim Project Groups. A physiologically based pharmacokinetic model for Valproic acid in adults and children. Eur J Pharm Sci 2014;63:45–52. 2. Skou JC. Consideration on bipolar maniodepressive disease and the effect of Lithium. A neurophysiological view on mental disorders. J Psychiatr Res 2015;61:237–238.
oxygen species (ROS) are produced. ROS modifies the redox status of protein, which, in turn, changes protein function. Indeed, patients with bipolar disorder (but not schizophrenia) are associated with decreased mitochondrial complex I activity (4) and increased oxidation of dopamine transporter, which demonstrates that oxidative modifications of dopaminergic proteins could underlie increased dopamine levels in mania (5). Animal (6) and cell (7) models have demonstrated the ability of valproate in preventing oxidative damage to proteins, suggesting that blockage of sodium channels not only prevents alterations of membrane potential (as described by Doctor Skou), but could also prevent oxidative modifications. Thus, it would be interesting to investigate whether sodium (and potentially potassium) channel blockers prevent changes to nerve membrane potentials via regulation of mitochondrial dysfunction. Doctor Skou’s suggestion that bipolar disorder is a membrane disease could help to integrate key findings and guide the discovery of potential new treatments for this illness.
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Copyright of Acta Psychiatrica Scandinavica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Acta Psychiatr Scand 2015: 131: 397–400 All rights reserved
ACTA PSYCHIATRICA SCANDINAVICA
Debate section Letters to the editor
Considerations on mental disorders: a neurophysiological approach DOI: 10.1111/acps.12409 It is interesting that anti-epileptica which are sodium channel blockers, for example valproate, have an effect both on epilepsy and on bipolar disorder (1). A sodium channel blocker decreases the permeability of membranes for sodium indicating that the two diseases are membrane diseases due to an increase in permeability of the membranes to sodium. The effect is selective. If it affects the sensory nerves, the disease is the bipolar manicdepressive disorder. If it affects the motoric nerves, it is epilepsy. An increase of nerve membranes permeability to sodium gives a decrease of the nerve membrane potential. At a low decrease, it becomes easier to trigger a nerve impulse, which means an increase in nerve irritability, which may explain a manic disorder. At a further decrease of the membrane potential, the nerve system irritability is decreased, which may explain a depressive disorder. The bipolar depressive disorder reacts to drugs which decreases the permeability to sodium, while the unipolar does not (2). Could it be that the unipolar depression also is due to a decreased membrane potential, but not due to an increase of nerve membranes to sodium, but to a decrease of permeability to potassium which also will give a decreased membrane potential?
DOI: 10.1111/acps.12410 Reply We read with interest Doctor Skou’s ‘Letter to Editor’ discussing the possibility that epilepsy and bipolar disorder are membrane diseases, based on his observations that attest to the efficacy of valproate to treat both diseases: Valproate blocks sodium channels leading to altered membrane potential (1). We note that epilepsy (2) and bipolar disorder (3) also manifest changes to mitochondrial function and consequently alterations to the redox state of proteins. These findings support Doctor Skou’s postulation of a common pathophysiology, albeit with different levels of system activation which in turn results in different clinical manifestations. In fact, it is expected that mania is associated with high levels of energy, or oxidative stress, whereas the opposite is expected for depression. Maintenance of proper mitochondrial function is essential for neuronal homeostasis and proper release of neurotransmitters (4). During oxidative phosphorylation, reactive
A test would be if potassium channel activators have an effect on the disease. A decrease of membrane potential can also be due to a combined effect of an increase in permeability to sodium and decrease of permeability to potassium. Could this give the very complex mental disorder schizophrenia? A test would be if a treatment with a sodium channel blocker plus a potassium channel activator has an effect on the disease. J. C. Skou University of Aarhus, Aarhus, Denmark E-mail: [email protected]
References 1. Ogungbenro K, Aarons L; CRESim & Epi-CRESim Project Groups. A physiologically based pharmacokinetic model for Valproic acid in adults and children. Eur J Pharm Sci 2014;63:45–52. 2. Skou JC. Consideration on bipolar maniodepressive disease and the effect of Lithium. A neurophysiological view on mental disorders. J Psychiatr Res 2015;61:237–238.
oxygen species (ROS) are produced. ROS modifies the redox status of protein, which, in turn, changes protein function. Indeed, patients with bipolar disorder (but not schizophrenia) are associated with decreased mitochondrial complex I activity (4) and increased oxidation of dopamine transporter, which demonstrates that oxidative modifications of dopaminergic proteins could underlie increased dopamine levels in mania (5). Animal (6) and cell (7) models have demonstrated the ability of valproate in preventing oxidative damage to proteins, suggesting that blockage of sodium channels not only prevents alterations of membrane potential (as described by Doctor Skou), but could also prevent oxidative modifications. Thus, it would be interesting to investigate whether sodium (and potentially potassium) channel blockers prevent changes to nerve membrane potentials via regulation of mitochondrial dysfunction. Doctor Skou’s suggestion that bipolar disorder is a membrane disease could help to integrate key findings and guide the discovery of potential new treatments for this illness.
397
Copyright of Acta Psychiatrica Scandinavica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
