EEG mapping and low-resolution brain electromagnetic tomography (LORETA) in diagnosis and therapy of psychiatric disorders: evidence for a key-lock principle.

Different psychiatric disorders, such as schizophrenia with predominantly positive and negative symptomatology, major depression, generalized anxiety disorder, agoraphobia, obsessive-compulsive disorder, multi-infarct dementia, senile dementia of the Alzheimer type and alcohol dependence, show EEG maps that differ statistically both from each other and from normal controls. Representative drugs of the main psychopharmacological classes, such as sedative and non-sedative neuroleptics and antidepressants, tranquilizers, hypnotics, psychostimulants and cognition-enhancing drugs, induce significant and typical changes to normal human brain function, which in many variables are opposite to the above-mentioned differences between psychiatric patients and normal controls. Thus, by considering these differences between psychotropic drugs and placebo in normal subjects, as well as between mental disorder patients and normal controls, it may be possible to choose the optimum drug for a specific patient according to a key-lock principle, since the drug should normalize the deviant brain function. This is supported by 3-dimensional low-resolution brain electromagnetic tomography (LORETA), which identifies regions within the brain that are affected by psychiatric disorders and psychopharmacological substances.     

Pharmaco-EEG in psychiatry.

In spite of its origins deeply rooted in the discipline, pharmaco-EEG applications in psychiatry remain limited to its achievements in the field of psychotropic drugs classification and, in few instances, discovery. In the present paper two attempts to transfer pharmaco-EEG methods to psychiatric clinical routine will be described: 1) monitoring of psychotropic drug toxicity at the central nervous system level, and 2) prediction of clinical response to treatment with psychotropic drugs. Both applications have been the object of several investigations providing promising and sometimes consistent findings which, however, had no impact on clinical practice. For the first topic, the review is limited to antipsychotics, lithium and recreational drugs, as for other psychotropic drugs mostly case studies are available, while for the response prediction it will include antipsychotics, antidepressants, anxiolytics, psychostimulants and nootropics. In spite of several methodological limitations, pharmaco-EEG studies dealing with monitoring of antipsychotic- and lithium-induced EEG abnormalities went close to, but never became, a clinical routine. EEG studies of recreational drugs are flawed by several limitations, and failed, so far, to identify reliable indices of CNS toxicity to be used in clinical settings. Several QEEG studies on early predictors of treatment response to first generation antipsychotics have produced consistent findings, but had no clinical impact. For other psychotropic drug classes few and inconsistent reports have appeared. Pharmaco-EEG had the potential for important clinical applications, but so far none of them entered clinical routine. The ability to upgrade theories and methods and promote large scale studies represent the future challenge.     

General anesthesia and long term psychotropic treatments]

Anesthesists often ask for withdrawal of psychotropic treatment a few days before surgery. Usually they do not differentiate among the various classes of psychotropic drugs. Some drugs, including MAO inhibitors and reserpine-like agents, can induce or precipitate accidents; however, this does not occur with other types of antidepressants, neuroleptics and minor tranquilizers. The authors review the psychiatric risks related to such withdrawals; these risks are to be considered. They report that in 8,210 ECT under general anesthesia (among which 5,688 were done without psychotropic withdrawal) there was no occurrence of severe accidents.     

Psychotropic drug use and correspondence with psychiatric diagnoses in the mental health in the general population survey

OBJECTIVES: The aims of this study were to assess the lifetime prevalence rate of psychotropic drugs use in the French general population and the correspondence between psychotropic drug use and psychiatric diagnoses. METHODS: Data were derived from the multicentric survey mental health in the general population, carried out in 47 French public sites between 1999 and 2003. A face-to-face questionnaire was used to interview a representative sample of French metropolitan subjects, aged 18 and over, noninstitutionalized or homeless. These subjects were recruited using quota sampling for age, sex, socioprofessional and education levels, according to data from the 1999 national French population census. Lifetime use of psychotropic drugs was explored by an open question. Psychiatric diagnoses were identified using the mini international neuropsychiatric interview (MINI). A national database was then constituted by pooling data from all sites, weighted for age, sex, level of education, socioprofessional level and work status, to be representative of the French general population. RESULTS: Of the 36785 individuals included in this study, more than one out of three subjects reported having used at least one psychotropic drug during their life. Anxiolytics were the most commonly used drugs, reported by 19.4% of the sample. The other frequently used psychotropic drugs were antidepressants (11.6%) and hypnotics (9.2%). Nearly half of the subjects with a MINI diagnosis reported no lifetime psychotropic drug use. Among the subjects meeting criteria for a diagnosis of mood disorder, 66.3% used psychotropic drugs. However, less than one out of three subjects with a diagnosis of major depressive disorder used antidepressants while 37.2% reported having used anxiolytics. Less than one out of four subjects with a diagnosis of anxiety disorder used antidepressants while 34.3% used anxiolytics. Among subjects with a diagnosis of anxiety disorder, antidepressants and anxiolytics were the most commonly used drugs for subjects with a diagnosis of panic disorder with agoraphobia (46.4 and 58.1%, respectively). Conversely, these were the treatments used the least by subjects with a diagnosis of generalized anxiety disorder (21.9 and 31.5%, respectively). Only 14.9% of subjects with a psychotic syndrome reported having used neuroleptics. Lastly, the highest proportion of subjects with at least one psychiatric diagnosis was found in mood stabilizer and neuroleptic users. However, one third of mood stabilizer users, a quarter of neuroleptic users and less than half of antidepressant and anxiolytic users presented no psychiatric disorder identified by the MINI. CONCLUSION: This study highlights the high frequency of exposure to psychotropic drugs in the general French population, and the marked inadequacy between the presence or absence of a psychiatric diagnosis and the lifetime presence or absence of a psychotropic drug treatment.     

Psychotropic drugs on general medical and surgical wards of a teaching hospital.

We examined the prescribing habits for psychotropic drugs of internists, surgeons, and gynecologists on their inpatient wards in a teaching hospital. Data were gathered from patients' charts and pharmacy records. In a six-week period, 9% of all admissions received such a drug. The male:female ratio and black:white ratios were studied; the maximum incidence of receiving these medications was in the 50- to 60-year age group. Minor tranquilizers were prescribed most frequently, followed, respectively, by major tranquilizers, barbiturates, and antidepressants. Less than half the available drugs were used, but drugs of differernt groups were often used interchangeably in an unsystematic fashion, and there was little evidence as to how effective a drug had been. It also seemed that depression was often overlooked or insufficiently treated.     

The AMUP study for drug surveillance in psychiatry - a summary of inpatient data

From 1979 to 1989 the AMUP study (AMUP = Arzneimittelüberwachung in der Psychiatrie) was conducted in two psychiatric hospitals in Germany with the aim to provide a systematic and standardized assessment of all adverse reactions to psychotropic drugs under conditions of routine practice. A total of 60.7 % of patients experienced at least one adverse drug reaction (ADR) with probable or definite causality during their stay in the hospital; 37.1 % of patients exhibited ADRs that had some therapeutic impact on further treatment. ADRs that led to drug discontinuation were observed in 8.6 %. This rate ranged from 9.5 to 5.1 % for haloperidol and perazine, the most common neuroleptics at that time; sedating antidepressants (AD) rated lower than non-sedating (amitriptyline 5.1 %, clomipramine 10.4 %). Lithium salts, antiparkinson drugs, and benzodiazepines were associated with considerably lower rates of ADRs than neuroleptics or antidepressants. Severe ADRs occurred in 1.4 % of exposed patients (e. g., toxic delirium, grand mal seizures, malignant neuroleptic syndrome, or agranulocytosis). The AMUP data suggest that administration of psychotropic drugs in psychiatric hospitals at that time was a safe, but also inconvenient treatment for many patients due to a wide range of bothersome side effects that compromised patient compliance. The data can serve as a reference base for comparisons with newer compounds introduced to the market over the last decade such as serotonin reuptake inhibitors (SSRIs) and other new AD, atypical neuroleptics, or other new generation psychotropic drugs.     

Hidden cardiac lesions and psychotropic drugs as a possible cause of sudden death in psychiatric patients: a report of 14 cases and review of the literature.

OBJECTIVE: To confirm the hypothesis that psychotropic drugs, especially neuroleptics, lithium, and antidepressants, are implicated as a cause of unexpected sudden death in psychiatric patients because of their cardiotoxicity, especially when hidden cardiac lesions are present. METHOD: We performed a full pathological examination of 14 psychiatric patients who unexpectedly and suddenly died between 1980 and 1999. RESULTS: Neuroleptics were involved in 13 instances, antidepressants in 9, and anxiolytics in 5. Psychotropic drugs were combined in all but a single patient. In all 14 patients, toxicological analyses discarded drug overdose as cause of death. At postmortem examination, the brain and abdominal organs were normal. In 13 patients, the following lesions were found in the heart and lungs: dilated cardiomyopathy (6 patients), left ventricular hypertrophy (2 patients, 1 of which was associated with mitral prolapse and anomalies of His bundle), arrhythmogenic cardiopathy of the right ventricle (1 patient), pericarditis (1 patient), mitral prolapse (1 patient), muscular bridge on the anterior interventricular artery (1 patient), and Mendelsons syndrome (1 patient). In 1 case, no changes were seen. Most of the drugs that were taken immediately prior to death can induce arrhythmias either by prolonging the QT interval, potentially resulting in torsades de pointes, or by widening QRS complexes, possibly leading to reentry and ventricular fibrillation. CONCLUSION: Our findings suggest that the arrhythmogenic effects of psychotropic drugs can be exacer bated when preexisting hidden cardiac lesions are present and can result in sudden death. Patients should be systematically evaluated for cardiac lesions prior to starting any treatment with psychotropic drugs; the minimal effective dosage should be used.     

Results of a brief survey on the prescribing practices for monoamine oxidase inhibitor antidepressants

Four hundred eighty-five psychiatrists in Pennsylvania and Delaware responded to a survey of prescribing practices for the monoamine oxidase inhibitor (MAOI) antidepressants. Although the low response rate (34%) limited the generalizability of the results, the similarity between respondents and the total sample surveyed argued against gross sampling bias. The authors found that only a minority of psychiatrists (25%) prescribe MAOIs regularly, despite a relatively low rate of reports of serious sequelae from hypertensive crises or other side effects. They also found that a substantial number of psychiatrists who regularly prescribe MAOIs also report prescribing high doses and combining therapy with tricyclics, lithium, neuroleptics, and psychostimulants. These findings have implications for postmarketing research on psychotropic drugs.     

Psychotropic drug withdrawal and the dexamethasone suppression test

In a prospective study of 25 patients from the time of hospitalization, seven had recently discontinued psychotropic agents (including antidepressants, neuroleptics, and benzodiazepines). All seven had positive dexamethasone suppression test results after 1 week of hospitalization. This phenomenon did not occur in any of the other subjects who had not discontinued such medications. Some of the subjects with postdexamethasone cortisol increases reported drug discontinuation in the drug histories they gave at admission, but in three, drug screening provided the only evidence of prior drug use. Medication withdrawal may be an underappreciated confounding variable in DST studies.     

The automated tail suspension test: A computerized device which differentiates psychotropic drugs

1. 1. Mice when suspended by the tail will alternate between active attempts to escape and immobility. Immobility like that measured in the behavioral despair test is reduced by a wide variety of antidepressant agents.

2. 2. The present paper describes a computerized version of this test (ITEMATIC-TST) which in addition to recording immobility measures the power of the movements.

3. 3. Various tricyclic (amitriptyline, desipramine, imipramine), MAOI (clorgyline, moclobemide, nialamide, pargyline, toloxatone) and atypical antidepressants (bupropion, citalopram, indalpine, miansenn, nomifensine, viloxazine) were tested and compared with psychostimulants (d-amphetamine, caffeine), neuroleptics (chlorpromazine, haloperidol, sulpiride), anxiolytics (clobazam, diazepam) and agents acting on the cholinergic system (atropine, oxotremorine).

4. 4. All antidrepressants decreased the duration of immobility and most increased the power of movements.

5. 5. The psychostimulants also decreased immobility but only amphetamine increased the power of movements.

6. 6. Neuroleptics increased immobility without affecting the power of movements, whereas anxiolytics increased immobility but decreased the power of movements.

7. 7. Atropine had a profile similar to antidepressants whereas oxotremorine tended to have opposite effects.

8. 8. The results suggest that the automated test system with its two parameters is not only sensitive to antidepressants but could also be useful for generating activity profiles for different kinds of psychotropic agent.

Influence of ocular filtering in EEG data on the assessment of drug-induced effects on the brain

Ocular artifacts in EEG signals affect the interpretation of clinical study results. The aim of this study was to assess the influence of automatic ocular filtering procedures in the conclusions drawn from a pharmaco-EEG trial. Regression analysis, gold standard, and blind source separation (BSS), Second Order Blind Identification algorithm, ocular filtering procedures were compared using time, frequency, topographic and tomographic brain mapping approaches and pharmacokinetic-pharmacodynamic (PK-PD) relationships. Data consisted of EEGs obtained from 20 volunteers who received single oral doses of haloperidol 3 mg, risperidone 1 mg, olanzapine 5 mg and placebo in a randomized cross-over double-blind design. Although the BSS-based technique preserved brain activity more than regression analysis in anterior leads, in general, topographic significance probability maps globally showed similar results with both methods for most spectral variables. However, different results were obtained when using whole multi-channel information for studying drug effects in the brain: (i) higher correlations between PK and PD time courses showing that BSS allowed estimation of spectral variables more accurately related to drug effects and (ii) larger and more symmetric drug related tomographic LORETA maps showing that BSS led to results that were more neurophysiopharmacologically sound. Definitely, the BSS-based procedure is an effective and efficient preprocessing method to remove ocular artifacts from EEG data. The selection of the ocular filtering procedure could determine different results whose impact depends on the evaluating tool applied to analyze the pharmaco-EEG data.     

The value of drug and metabolite concentration in blood as a biomarker of psychopharmacological therapy

Abstract

Desirable and undesirable effects of a drug are related to its concentration at various sites of actions. For many psychotropic drugs, it has been shown that drug concentration in brain correlates with concentration in blood. The latter is also an available estimate of clearance and bioavailability. Its monitoring enables identification of multiple factors that have an impact on clinical outcomes, especially uncertain compliance and pharmacokinetic peculiarities. For this review we analysed for antidepressants if drug concentration in blood can be used as biomarker for psychopharmacological treatment. Systematic review of the literature revealed for new and old antidepressant drugs that drug and metabolite concentrations in blood are measures of the pharmacokinetic phenotype and related differentially to occupancy of primary target structures, therapeutic effects and unwanted anticholinergic, cardiac and other side effects. Drug concentration in blood can therefore be used as biomarker in clinical practice to guide psychopharmacological treatment with established antidepressant drugs. Monitoring of drug concentration is suitable to improve efficacy and safety of the pharmacotherapy, especially in elderly patients who require complex pharmacological therapies.     

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.