Effectiveness and neuropsychiatric side effects of anticonvulsant drugs in psychiatric disorders and epilepsy

The anticonvulsant drugs exhibit a wide range of effectiveness in several neurological (i.e. neuropathic pain, migraine) and psychiatric disorders due to their actions on:

a) Neurotransmitter metabolism. The agonistic effects on the GABAergic system is related to the anxiolytic properties of tiagabine, vigabatrine and benzodiazepines. The increase of extracellular serotonin and the modulation of serotoninergic transmission by carbamazepine, oxcarbazepine and valproate may play a crucial role in the control and prevention of impulsivity and violent behavior in patients with borderline or antisocial personality disorder. The inhibition of the release of glutamate and asparate by lamotrigine may be related to its antidepressant efficacy in bipolar patients,

b) Voltage-gated ion channels. The inhibition of sodium influx as well as the blockade of sodium and calcium channels, which is observed in several antiepileptic agents (carbamazepine, oxcarbazepine, valproate, lamotrigine, topiramate) is closely related to their antimanic and mood stabilizing properties. Gabapentin and pregabalin present anxiolytic properties by blocking a2-d-type calcium channels and

c) Second messenger systems such as the inositol phospholipid pathway, the Na+K+ATPase and adenylate cyclase activity and the protein kinase activity. Carbamazepine and valproate have been proven effective as anti-manic and mood stabilising agents. Furthermore, they are considered superior than lithium for the treatment and prevention of rapid-cycling bipolar disorder and mixed episodes (dysphoric mania). Lamotrigine exhibits antidepressant properties and has been approved for the treatment of both bipolar II disorder and bipolar depression. Oxcarbazepine is widely used for the control of impulsive aggression ecpecially in patients with dementia and borderline or antisocial personality disorder. Other second generation anticonvulsants such as pregabalin, gabapentin show promise for their anxiolytic effects. Gabapentin in high doses may be effective in social anxiety disorder. On the other hand, pregabalin has been proven equally effective to SSRI'S or venlafaxine for the treatment of generalized anxiety disorder. Carbamazepine, oxcarbazepine and gabapentin are widely used for the prevention and treatment of alcohol or benzodiazepines withdrawal. Furthermore, topiramate may be useful for the treatment of alcoholism. However, most of the anticonvulsant agents may cause neuropsychiatric side effects, such as cognitive impairment, depression, anxiety, insomnia, behavioral disorders, learning disabilities and psychosis. Mechanisms which may be related to the pathogenesis of such adverse effects include pharmacodynamic problems, dosage-dependent toxic effects, idiosyncratic effects, "forced normalisation" and drug withdrawal. These side effects vary according to the specific anticonvulsant agent. For example valproate may cause encephalopathy, phenytoin is related to psychotic symptoms and benzodiazepines and barbiturates frequently cause sedation, rebound insomnia, withdrawal syndromes and anterogade amnesia. Depression is the most common side effect of the antiepileptic therapy, ecpecially with agents such as tpiramate, levetiracetam, tiagabine and vigabatrine. Psychotic symptoms are much less common and they usually subside after the discontinuation of the antiepileptic agent (mainly topiramate and vigabatrine). The initiation of therapy with lamotrigine may cause transient anxiety and insomnia. Finally, levetiracetam and to a much lesser extent, vigabatrine may be responsible for behavioral disorders, ecpecally in patients with previous psychiatric history or mental retardation. Therefore, the coexistence of epilepsy with psychiatric disorders and the possible psychiatric side effects of the anticonvulsant treatment may play a crucial role for the selection of the suitable anticonvulsant agent. Encephalos 2009, 46(1):35-39.

Key words: Anticonvulsant drugs, psychiatric disorders, epilepsy, mechanisms of action, effectiveness, neuropsychiatric side effects.