Reduced habituation of auditory evoked potentials indicate cortical hyper-excitability in Fragile X Syndrome.

Sensory hypersensitivities are common, clinically distressing features of Fragile X Syndrome (FXS). Preclinical evidence suggests this abnormality may result from synaptic hyper-excitability in sensory systems. This model predicts reduced sensory habituation to repeated stimulus presentation. Fourteen adolescents and adults with FXS and 15 age-matched controls participated in a modified auditory gating task using trains of 4 identical tones during dense array electroencephalography (EEG). Event-related potential and single trial time-frequency analyses revealed decreased habituation of the N1 event-related potential response in FXS, and increased gamma power coupled with decreases in gamma phase-locking during the early-stimulus registration period. EEG abnormalities in FXS were associated with parent reports of heightened sensory sensitivities and social communication deficits. Reduced habituation and altered gamma power and phase-locking to auditory cues demonstrated here in FXS patients parallels preclinical findings with Fmr1 KO mice. Thus, the EEG abnormalities seen in FXS patients support the model of neocortical hyper-excitability in FXS, and may provide useful translational biomarkers for evaluating novel treatment strategies targeting its neural substrate.

Antipsychotic medications and the elderly: effects on cognition and implications for use.

Despite being frequently prescribed in the elderly, antipsychotic medications are commonly associated with adverse effects in this population, including sedative, orthostatic and extrapyramidal adverse effects. Growing evidence suggests that antipsychotics can also cause deleterious cognitive effects in some elderly patients. Preclinical and growing clinical evidence indicates that inhibitory effects on dopaminergic, cholinergic and histaminergic neurochemical systems may account for antipsychotic-associated cognitive impairment in the elderly. A review of published reports of the cognitive effects of antipsychotics in the elderly suggests that newer antipsychotic medications may possess a more favourable cognitive profile than that of traditional agents in this population. The cognitive effect that a specific antipsychotic will have in the elderly, however, is likely better predicted by considering the pharmacodynamic action of an individual agent in combination with the pathophysiology of the condition being treated. Agents with relatively weak dopamine inhibiting effects (e.g. clozapine and quetiapine), for example, would theoretically have a cognitive profile superior to that of agents with higher degrees of dopaminergic inhibition (all traditional agents, risperidone, olanzapine and ziprasidone) when used for conditions associated with diminished dopamine function (e.g. idiopathic Parkinson's disease). Drugs with weak anticholinergic effects (high-potency traditional agents, risperidone, quetiapine and ziprasidone) would theoretically be less likely to cause cognitive impairment than agents with high degrees of cholinergic receptor blocking actions (clozapine and olanzapine) when treating patients with impaired cholinergic function (e.g. Alzheimer's disease). Cholinergic agonist effects of clozapine and olanzapine may, however, mitigate potential adverse cognitive effects associated with the cholinergic blocking actions of these agents. Large, rigorous trials comparing the cognitive effects of antipsychotics with diverse pharmacodynamic actions are lacking in the elderly and are needed.

Pharmacokinetics of clozapine and risperidone: a review of recent literature.

The current literature describing the pharmacokinetics of the atypical antipsychotics clozapine and risperidone is reviewed, and discussion on the clinical significance of these data is presented. These drugs are well absorbed when taken orally but are poorly bioavailable because of presystemic elimination. They are highly cleared by hepatic metabolism involving specific P450 isozymes. Risperidone elimination produces a potent active metabolite. Neither of the drugs has received extensive study related to drug-drug interactions, but several are potentially important because a purported therapeutic plasma concentration range is proposed for clozapine and a possible curvilinear dose response relationship has been reported for risperidone. The current clinical pharmacokinetic database for these atypical antipsychotics suggests that much can be learned with additional study that would be of value in individualizing their dosage regimens.

Secondary mania: diagnosis and treatment.

Increasing evidence indicates that subtypes of bipolar disorder differ not only in symptomatology and associated clinical features, but by differences in age at onset, illness course, and response to treatment. Secondary manic states differ from typical bipolar states and are often especially difficult to treat. Although the correction of the underlying organic factors (toxic, metabolic, or infectious) may effectively reverse the manic presentation, many organic factors are not reversible (trauma, stroke, and aging), and the presence of these etiologic factors can complicate traditional antimanic treatments. Lithium may be effective for treating patients with secondary mania, but data from published studies show that in this population the associated adverse effects often limit its usefulness. Anticonvulsants appear to offer an effective alternative. Divalproex sodium, in particular, has been shown to be an effective and well-tolerated treatment in open trials in the elderly and other patient groups with secondary mania. Controlled clinical trials are necessary to confirm the efficacy and tolerability of mood-stabilizing anticonvulsants in the treatment of secondary mania.