Journal of Clinical EEG & Neuroscience, January 2004
Current and Future Therapeutic Opportunities in the Comorbidity Between the Epilepsies and Affective Disorders
Phillip C. Jobe, Guest Editor
|Current Status of the Utilization of Antiepileptic Treatments in Mood, Anxiety and Aggression: Drugs and Devices
John J. Barry, Anna Lembke and Kim D. Bullock
|Convergences in Course of Illness and Treatments of the Epilepsies and Recurrent Affective Disorders
Robert M. Post and Susan R. B. Weiss
|Shared Mechanisms of Antidepressant and Antiepileptic Treatments: Drugs and Devices
Phillip C. Jobe
|Epilepsy and Depression: Imaging Potential Common Factors
William H. Theodore
|Structural MRI Changes of the Brain in Depression
Andres M. Kanner
|Affective Disorder and Epilepsy Comorbidity: Implications for Development of Treatments, Preventions and Diagnostic Approaches
Phillip C. Jobe
Interventions that have been utilized to control seizures in people with epilepsy have been employed by the psychiatric community to treat a variety of disorders. The purpose of this review will be to give an overview of the most prominent uses of antiepileptic drugs (AEDs) and devices like the Vagus Nerve Stimulator (VNS) and Transcranial Magnetic Stimulation (TMS) in the treatment of psychiatric disease states. By far, the most prevalent use of these interventions is in the treatment of mood disorders. AEDs have become a mainstay in the effective treatment of Bipolar Affective Disorder (BAD). The U.S. Food and Drug Administration has approved the use of valproic acid for acute mania, and lamotrigine for BAD maintenance therapy. AEDs are also effectively employed in the treatment of anxiety and aggressive disorders. Finally, VNS and TMS are emerging as possibly useful tools in the treatment of more refractory depressive illness.
The failure to achieve and maintain remission is a critical problem for a high percentage of patients with epilepsy and the primary affective disorders. Early illness onset and delayed initiation of treatment may contribute to primary treatment resistance or that associated with loss of efficacy (tolerance phenomenon).
Neurobiological data and principles drawn from the amygdala kindling model of seizure progression are reviewed for their heuristic value in conceptualizing molecular mechanisms of illness progression and its prevention with pharmacological agents in the epilepsies and, indirectly, the recurrent affective disorders. Caveats in the use of this model and convergences and divergences in its predictive validity for seizures and affective disorders are noted.
Many treatments for the epilepsies and affective disorder share the properties of seizure suppression and mood stabilization. Moreover, affective disorders and the epilepsies appear to share partially similar pathogenic mechanisms. A component of the shared predisposition appears to arise from noradrenergic and serotonergic deficits. Increasing evidence supports the hypothesis that noradrenergic and/or serotonergic elevation is a mechanism of therapeutic benefit shared by most antidepressants and many antiepileptic medications. Medication induced alterations in GABAergic, glutamatergic, and CRH (corticotropin releasing hormone) containing neurons may also contribute to the shared therapeutic properties of antidepressant and antiepileptic medications.
Patients with seizure disorders have an increased incidence of depression. This may be due in part to psychosocial factors, or side effects of antiepileptic drugs. However, there may be underlying physiologic mechanisms for the relationship. Neuroimaging studies, including structural magnetic resonance imaging, positron emission tomography measurements of cerebral glucose metabolism, and, more recently, imaging of serotonin 1A receptors, may provide additional data to explain overlapping clinical manifestations of epilepsy and depression.
For many years, investigators have been trying to identify the neuroanatomical structures responsible for the development of neuropsychiatric disorders, specifically depression and schizophreniform disorders. The available data were based on observations made in neurological patients who developed a psychiatric comorbid disorder following the neurologic insult. With the advances in high-resolution magnetic resonance imaging and functional neuroimaging studies, we have witnessed in the last decade a wealth of new data that identify structural neuroimaging changes in mesial temporal structures, prefrontal cortex and basal ganglia in major depressive disorders. The purpose of this article is to briefly review the publshed data on neuroanatomical structural changes associated with major depressive and bipolar disorders.
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 antidepressants. 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 b-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.