title: Affective disorder and epilepsy comorbidity: implications for development of treatments, preventions and diagnostic approaches.
abstract: Concepts pertaining to affective disorder and epilepsy comorbidity are contributing appreciably to improvements in patient care. Several antiepileptic treatments have become important components of the management of bipolar affective disorder. In contrast, little progress has emerged in developing clinical applications of the anticonvulsant properties of the antidepressants in the treatment of the epilepsies. The slow onset of action of the antidepressants remains a major impediment to fully effective treatment of depressive episodes. Nevertheless, studies from experimental epileptology demonstrate that the anticonvulsant effects of the antidepressants occur rapidly and as a consequence of noradrenergic and/or serotonergic activation. These studies also demonstrate that adequate initial doses of the antidepressants are essential to rapid onset of anticonvulsant action. Pharmacokinetically valid loading dose paradigms are seemingly avoided with antidepressant drugs in humans because of potential toxicities and/or patient unacceptability. However, substantial progress has been made in reducing the adverse effect liability of the antidepressants. No longer is convulsive liability considered to stem from the therapeutic mechanisms of the anti-depressants. Rather, noradrenergic and serotonergic influences have demonstrable anticonvulsant properties. Other side effects may also be separable from the anticonvulsant and antidepressive effects of antidepressive treatments. The concept that the protracted process of antidepressant-induced beta-noradrenergic down-regulation is an essential prelude to the onset of mood benefit is no longer a sustainable premise. Nevertheless, increasing evidence underlies the possibility that knowledge of serotonergic and noradrenergic regulatory processes can be used to design strategies that will hasten the onset of antidepressive action. Similar optimism pervades efforts to determine the possibility that dual inhibition of serotonin and norepinephrine transporters will hasten onset of antidepressive action. Moreover, because noradrenergic and serotonergic systems are determinants of predisposition to seizures and to dysfunctional affective episodes, augmentation strategies may also be applicable to the use of antidepressant drugs in epilepsy and to the use of antiepileptic drugs such as carbamazepine in mood disorders. Recent studies have demonstrated that, in part, the therapeutic effectiveness of carbamazepine may stem from its marked capacity to elevate serotonin concentrations in the extracellular fluid of the brain via mechanisms that differ from those of the membrane reuptake inhibitors. Evidence suggests that the epilepsies and affective disorders may arise from a multiplicity of neurobiological abnormalities. A disorder in one individual may arise via different mechanisms than a phenomenologically similar disorder in another individual. Thus, diagnostic tools are needed to make mechanistic distinctions among individuals so that treatments can be appropriately developed and selected. In terms of epileptogenesis and affective disorder progression, neuroprotective paradigms for one individual may differ from those needed for another. Moreover, diagnostic technologies that are adequate to detect genetically and/or experientially determined vulnerability before the onset of a seizure or dysfunctional affective episode may be valuable steps toward achieving goals of prevention.
authors.affiliation: Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine, PO Box 1649, Peoria, Illinois 61656-1649, USA. pcj@uic.edu
authors.forename: Phillip C
authors.initials: PC
authors.lastname: Jobe
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects; D015897:Comorbidity; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D006801:Humans; D019964:Mood Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D009415:Nerve Net / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D000928:Antidepressive Agents; D018377:Neurotransmitter Agents