Kenneth Alper

Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports.

BACKGROUND Clinical trial data provide an approach to the investigation of the effects of psychopharmacological agents, and psychiatric disorders themselves, on seizure threshold. METHODS We accessed public domain data from Food and Drug Administration (FDA) Phase II and III clinical trials as Summary Basis of Approval (SBA) reports that noted seizure incidence in trials of psychotropic drugs approved in the United States between 1985 and 2004, involving a total of 75,873 patients. We compared seizure incidence among active drug and placebo groups in psychopharmacological clinical trials and the published rates of unprovoked seizures in the general population. RESULTS Increased seizure incidence was observed with antipsychotics that was accounted for by clozapine and olanzapine, and with drugs indicated for the treatment of OCD that was accounted for by clomipramine. Alprazolam, bupropion immediate release (IR) form, and quetiapine were also associated with higher seizure incidence. The incidence of seizures was significantly lower among patients assigned to antidepressants compared to placebo (standardized incidence ratio = .48; 95% CI, .36- .61). In patients assigned to placebo, seizure incidence was greater than the published incidence of unprovoked seizures in community nonpatient samples. CONCLUSIONS Proconvulsant effects are associated with a subgroup of psychotropic drugs. Second-generation antidepressants other than bupropion have an apparent anticonvulsant effect. Depression, psychotic disorders, and OCD are associated with reduced seizure threshold.

Neuroinflammation and psychiatric illness

Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). Investigations into the pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review the link between autoimmunity and neuropsychiatric disorders, and the human and experimental evidence supporting the pathogenic role of neuroinflammation in selected classical psychiatric disorders. Understanding how psychosocial, genetic, immunological and neurotransmitter systems interact can reveal pathogenic clues and help target new preventive and symptomatic therapies.

Nonepileptic seizures and childhood sexual and physical abuse

Nonepileptic seizures (NES) must be distinguished from epilepsy to avoid the adverse effects of unnecessary antiepileptic drugs and to initiate appropriate psychiatric treatment. A higher frequency of prior sexual abuse has been suspected in NES, although no prospective controlled study has compared patients with NES and epilepsy, A series of patients with conversion disorder presenting as epilepsy and 140 patients with complex partial epilepsy (CPE) without evidence of conversion were selected from a series of consecutive admissions to a comprehensive epilepsy center. The groups did not differ with respect to age, years of education, race, or marital status, but the percentage of women was greater in the conversion NES group (73.2%) than in the CPE control group (50.7%; p < 0.002). The frequency of a history of sexual or physical abuse was greater in the NES group (32.4%) than in the CPE controls (8.6%; p < 0.000). Severity of sexual but not physical abuse was significantly greater in the NES group relative to controls (p < 0.05). There was a trend for a closer relationship of the perpetrator of sexual abuse to the victim among the NES patients compared with CPE controls (p < 0.1). These results support the impression that childhood abuse is more common among patients with conversion NES than with epilepsy, and suggests that in some cases childhood abuse may be a contributory pathogenetic factor.

Quantitative EEG correlates of cognitive deterioration in the elderly

We report on the quantitative analysis of the EEG (QEEG), using the Neurometric method, in large samples of normal elderly; normal subjectively impaired elderly; patients with mild cognitive impairment; patients presenting with a continuum of primary cognitive deterioration from mild to moderately severe as measured by the Global Deterioration Scale (GDS), compatible with dementia of the Alzheimers type (DAT). Neurometric QEEG measures were found to be a sensitive index of degree of cognitive impairment, especially reflected in increased absolute and relative power in the theta band, with delta increasing in later stages of deterioration. While these abnormalities were widespread, neither localized or lateralized, MANOVAs for GDS and relative power in theta reached highest significance in a bilateral temporo-parietal arc. A possible relationship between hippocampal dysfunction, cognitive deterioration, and theta abnormalities is discussed in relation to these findings. The results suggest that Neurometric QEEG features are sensitive to the earliest presence of subjective cognitive dysfunction and might be useful in the initial evaluation of patients with suspected dementia, as well as in estimating the degree of cognitive deterioration in DAT patients.

Treatment of Acute Opioid Withdrawal with Ibogaine

Ibogaine is an alkaloid with putative effect in acute opioid withdrawal. Thirty-three cases of treatments for the indication of opioid detoxification performed in non-medical settings under open label conditions are summarized involving an average daily use of heroin of .64 +/- .50 grams, primarily by the intravenous route. Resolution of the signs of opioid withdrawal without further drug seeking behavior was observed within 24 hours in 25 patients and was sustained throughout the 72-hour period of posttreatment observation. Other outcomes included drug seeking behavior without withdrawal signs (4 patients), drug abstinence with attenuated withdrawal signs (2 patients), drug seeking behavior with continued withdrawal signs (1 patient), and one fatality possibly involving surreptitious heroin use. The reported effectiveness of ibogaine in this series suggests the need for systematic investigation in a conventional clinical research setting.

Postictal psychosis: A case control series of 20 patients and 150 controls

We compared clinical data, EEG, and video-EEG studies in a consecutive series of 20 patients with postictal psychosis (PP) to 150 consecutive epilepsy patients with complex partial (CPS) or generalized tonic-clonic (GTCS) seizures but without PP. There was a lucid interval between last seizure and onset of psychosis ranging from 2.3 to 72 h (mean, 25 h). Duration of PP ranged from 16 to 432 h (mean, 83 h). Age, sex, epilepsy type (partial vs. generalized), and history of febrile seizures were similar in the PP and control groups. Patients with PP had more frequent GTCS during monitoring than controls (2.8 vs. 1.3; P < 0.001). Patients with PP were more likely to have a history of encephalitis (P < 0.0001) and psychiatric hospitalization (P < 0.002). More patients with PP had bilateral interictal epileptiform discharges during monitoring than controls (P < 0.0002). Postictal psychosis most often develops in patients with bilateral dysfunction following a cluster of GTCS.

Quantitative electrophysiological characteristics and subtyping of schizophrenia.

Quantitative descriptors of resting electroencephalogram (EEG) (QEEG) and event-related potentials (QERP) to visual and auditory stimuli were obtained from normal subjects and 94 chronic schizophrenic patients on medication, 25 chronic schizophrenics off medication, and 15 schizophrenics with no history of medication. These schizophrenic groups showed a high incidence of neurometric features that were significantly deviant from normative values. Multivariate discriminant analysis using these features successfully separated the schizophrenic patients from normals with high accuracy in independent replication. The data from the medicated group were subjected to cluster analysis. Newly developed algorithms were used for objective selection of the most effective set of variables for clustering and the optimum number of clusters to be sought. Five clusters were obtained, containing roughly equivalent proportions of the sample with markedly different QEEG profiles. The whole sample was then classified into these clusters. Each cluster contained patients both on and off medication, but patients who had never been medicated were classified into only three of these clusters. No significant clinical or demographic differences were found between members of the five clusters; however, clear differences in QERP profiles were seen. These results are described in detail and possible physiological and pharmacological implications are discussed.

Dissociation in Epilepsy and Conversion Nonepileptic Seizures

Summary: Purpose: We examined the dimensionality of the item content of the Dissociative Experiences Scale (DES) in relation to the clinical diagnosis of conversion nonepileptic seizures (C‐NES) versus complex partial epilepsy (CPE).

Clinical profile of patients with epileptic and nonepileptic seizures

Epileptic seizures (ES) and nonepileptic seizures (NES) often coexist in patients with treatment-refractory seizures. There are few data on ictal features of these different seizure types in the same patient. We identified 20 patients with ES from a group of 99 NES patients (ES/NES) and compared this group with patients with only ES or NES. All 20 ES/NES patients developed NES after ES. Clinical features of NES clearly differed from ES in 18 of 20 cases. In patients with ES/NES their ES were similar to seizures in patients with only ES, and their NES were similar to spells in patients with only NES. ES/NES patients were similar to ES patients in electrodiagnostic and neuroimaging studies, and similar to NES patients in psychiatric interviews and inventories. The clinical manifestations of ES and NES in the same patient are usually different. Both types of events may be stereotypic and can be distinguished and characterized during video-EEG recording. Determining what events are more prevalent or disturbing is critical. Psychiatric and antiepileptic drug treatment may be provided accordingly. NEUROLOGY 1996;46: 1530-1533

Chapter 1 Ibogaine: A review

Publisher Summary The chapter discusses ibogaine, which is a naturally occurring plant alkaloid with a history of use as a medicinal and ceremonial agent in West Central Africa and has been alleged to be effective in the treatment of drug abuse. The National Institute on Drug Abuse (NIDA) has given significant support to animal research, and the U.S. Food and Drug Administration (FDA) has approved Phase I studies in humans. The chapter discusses the first International Conference on Ibogaine. A major focus of the Conference was the possible mechanism(s) of action of ibogaine. Another important focus of the Conference was to discuss human experience with ibogaine and preclinical and clinical evidence of efficacy and safety. The Conference also featured presentations related to the sociological and anthropological aspects of the sacramental context of the use of iboga in Africa and the distinctive ibogaine subculture of the U.S and Europe. Ibogaine is the most abundant alkaloid in the root bark of the Apocynaceous shrub Tabernanthe iboga , which grows in West Central Africa. The chapter presents a timeline that outlines the historical events relating to the development of ibogaine as a treatment for drug dependence. Ibogaine and serotonin both contain an indole ring in their structure, and ibogaine has been shown to bind to the serotonin transporter and to increase serotonin levels in the nucleus accumbens (NAc). Stereotypy is a methodologic issue that might explain some of the disparate results regarding ibogaines interaction with the locomotor response to cocaine.