Clobazam, Oxcarbazepine, Tiagabine, Topiramate, and Other New Antiepileptic Drugs

Summary: Clinical investigators recently have studied at least 21 new antiepileptic drugs (AEDs) in people with epilepsy. This review briefly examines 15 of these new AEDs: clobazam (CLB), dezinamide, flunarizine (FNR), loreclezole, milacemide (MLM), MK-801, nafimidone, ORG-6370, oxcarbazepine (OCBZ), progabide (PGB), ralitoline, stiripentol, tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS). CLB, PGB, and TGB represent agents that act on the GABA system, and MLM acts on the glycine system. MK-801 and ZNS (in part) are excitatory amino acid antagonists, and FNR is a calcium-channel antagonist. OCBZ is a keto analogue of carbam-azepine, which is not metabolized to the epoxide and may have fewer side effects. The remaining agents are novel compounds with a variety of suspected mechanisms. TPM appears especially effective for intractable partial seizures but has a high incidence of cognitive side effects. None of these new AEDs is useful for all patients with inadequate seizure control or ongoing toxicity. The role of each will require further clinical study and experience.     

Consecutive Gas Chromatographic Determination of Phenytoin, Phenobarbital, Primidone, Phenylethylmalondiamide, Carbamazepine, Trimethadione, Dimethadione, Ethosuximide, and Valproate from the Same Serum Specimen

A quantitative gas-liquid chromatographic procedure is described for the consecutive determination of phenytoin, phenobarbital, primidone, phenylethylmalondiamide, carbamazepine, trimethadione, dimethadione, ethosuximide and valproate from a single serum specimen of 1.2 ml. After extraction from serum by two different procedures, the anticonvulsants are chromatographed without further purification on a 3% OV 17 column either with or without derivative formation by means of "on-column" methylation. Multiple internal standards are employed in order to enhance the reproducibility of drug-concentration measurement.     

Frontal lobe psychopathology: mania, depression, confabulation, catatonia, perseveration, obsessive compulsions, and schizophrenia

The frontal lobes can be subdivided into major functional neuroanatomical domains, which, when injured, surgically destroyed, or reduced in activity or volume, give rise to signature pathological and psychiatric symptomology. A review of case reports and over 50 years of research, including magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography scans, indicates that apathy, "blunted" schizophrenia, major depression, and aphasic-perseverative disturbance of speech and thought are associated with left lateral as well as bilateral frontal (and striatal) abnormalities. Impulsiveness, confabulatory verbosity, grandiosity, increased sexuality, and mania are associated with right frontal (as well as bilateral) disturbances. Gegenhalten, catatonia, and disturbances of "will" are indicative of medial frontal injuries. Disinhibitory states and obsessive-compulsive perseverative abnormalities are more frequently observed with orbital frontal lobe dysfunction, including frontal-striatal disturbances. These associations, however, are not always clear-cut as patients with the same diagnosis may demonstrate different symptoms that may be due to an additional abnormality in a different region of the brain. Moreover, as the frontal subdivisions are richly interconnected, and as frontal lobe abnormalities are not always discrete or well localized, a wide array of seemingly divergent waxing and waning symptoms may be manifest, sometimes simultaneously, including manic depression and what has been referred to as the "frontal lobe personality."     

Customer, Client, Consumer, Recipient, or Patient

Since the arrival of managed care, there has been a trend toward changing the basic terminology used to address clinicians and patients. Instead of the term patient, third party payors frequently use terms such as customer, client, consumer or recipient. One study demonstrated that patients prefer to be called patients. To investigate the preferred term to refer to patients and to be referred to by patients, we mailed a questionnaire to 100 physicians in four medical specialties each and to 100 psychologists. The overall response rate was 61%. Physicians overwhelmingly preferred to refer to patients by the patient's last name, their second preference was the patient's first name. Psychologists preferred to refer to the patients by first name, their second preference was the patient's last name. No group favored using terms such as client, customer, consumer, or recipient. Most physicians and psychologists preferred being referred to as doctors and nobody favored the term provider.     

Autism, amnesia, hippocampus, and learning.

Autism is held to be the result of the failure of a central cognitive processor which is necessary for flexible multidimensional association of sensorial stimuli, memory, and motivational states. Failure of this processor produces rigid, invariant, rote behavior, thought and language and aberrant modulation of emotion. It is argued that this central processing function is critically dependent on the hippocampus. Thus autism is postulated to be the developmental syndrome of hippocampal dysfunction. The hippocampus is postulated to be necessary for normal development in the child of language syntax, semantics, and pragmatics; the capacity for creativity and generativity in language and behavior, and combinatorial possibilities in general; for the integration of motivational states with experience and learning; and for the construction of a complex, useful and flexible structure of meaning. These constructs may become independent of hippocampus for use, but hippocampus is still required to modify or add to them. Finally, this analysis suggests a specific hypothesis of hippocampal organization which I advance as an hypothesis: that the hippocampus can be modelled as a multidimensional system in which the unique intersection of all input dimensions is the resultant.     

Locked-in Syndrome,BCI, and a Confusion about Embodied,Embedded, Extended,and Enacted Cognition

In a recent contribution to this journal, Andrew Fenton and Sheri Alpert have argued that the so-called “extended mind hypothesis” allows us to understand why Brain Computer Interfaces (BCIs) have the potential to change the self of patients suffering from Locked-in syndrome (LIS) by extending their minds beyond their bodies. I deny that this can shed any light on the theoretical, or philosophical, underpinnings of BCIs as a tool for enabling communication with, or bodily action by, patients with LIS: BCIs are not a case of cognitive extension. I argue that Fenton and Alpert’s claim to the contrary is the result of a widespread confusion about some related, but significantly different, approaches to cognition that all fall under the heading of “situated cognition.” I first provide a short taxonomy of various situated approaches to cognition, highlighting (some of) their important commonalities and differences, which should dissolve some of the confusions surrounding them. Then I show why the extended mind hypothesis is unsuitable as a model of BCI enhancements of LIS patients’ capacity to interact with their surroundings, and I argue that the situated approach with obvious bearings on the sort of questions that were driving Fenton and Alpert is not the idea that cognition is extended, but the idea that cognition is enacted.     

Diabetes mellitus,insulin resistance,hyperglycemia, and stroke

It is well established that diabetes is associated with an increased risk of stroke. Once a stroke has occurred, patients with diabetes experience poorer outcomes (functional status, mortality). Convincing data now support aggressive glucose control and comprehensive cardiovascular risk factor management to prevent stroke in patients with diabetes. However, there remains a distinct paucity of information concerning secondary stroke prevention. Hyperglycemia in the acute stroke setting is a marker for poor outcomes, but it remains unclear whether intensive in-hospital lowering of blood glucose levels improves clinical outcomes. Targeting insulin resistance as a modifiable risk factor for stroke is a novel strategy currently under investigation.     

Insomnia: prevalence, impact, pathogenesis, differential diagnosis, and evaluation.

When patients report problems sleeping, a psychiatrist must determine their significance based on frequency, duration, and daytime impairment. Because up to 50% of adults report sleep problems in any year, it is necessary to define when insomnia becomes long-standing, severe, and a complication to daytime function. Psychiatrists must determine if a sleep disturbance reduces mood, motor performance, or cognitive function. If insomnia syndrome is present, major depression, dysthymia, and anxiety disorders commonly are comorbid. To assist in evaluating insomnia, psychiatrists are urged to use the 6 Ps + M of insomnia model to conceptualize the characteristics of the insomnia and coordinate therapeutic intervention.     

Attachment,Abandonment, Murder

Alma phoned me, introduced herself, and started crying. She said that she had been referred to me because a terrible thing had happened. As I would later learn, we were about to deal with a wordless breakdown; a patient preoccupied with an object's “death” and her own destructive power. Using a relational perspective, this article will address concepts of separation and loss related to insecure attachment. We will focus on the emotional engulfment and anxiety associated with abandonment and loss as they arise in the therapeutic relationship. Fantasies related to the destructive power of need will be explored, including the fantasy of weaning from the object as from drugs, food, or alcohol, the confusion between murder and abandonment—the former stemming not from hatred but rather from love—and this confusion as expressed in the therapeutic dyad. The article concludes with the patient's response to her case presentation.     

Alzheimer, famille, institution

Alzheimer's disease (AD) is a dementia in which symptoms include cognitive impairment and also behaviour and psychological disorders. A study on the family's responses to the AD of a relative, requires envisaging several points of view. a) The family's burden. The caregiver who is generally a spouse, a daughter or a daughter-in-law has to perform difficult tasks. Caring for a patient with AD the caregiver faces a loss of role and reference. The patient's child is often playing the role of parent of the parent. Dementia caregiving exposes to high levels of stress and has psychiatric and physical effects on the caregiver, who is likely to suffer from anxiety, depression, alcoholism, and have an increased risk of mortality. Institutionalisation is a step of critical importance in AD care; the decision has to be made by the family, at the right time; b) The family's responses to AD symptoms. The family has to bear the AD symptoms: cognitive symptoms and above all, behavioural and psychological symptoms. The family senses the diagnosis when the first disorders appear in daily life. Then a large part of the family's history is lost, as the patient becomes unable to talk about the present and the past experience. In AD, the psychological disorders are: depression, anxiety, psychotic disorders and delirium. And in several psychotic disorders, the family may be involved: hallucinations, delusions particularly with ideas of theft, abandonment, jealousy or misidentification. But the most difficult problems are those of behavioural disorders; the family has to face agitation, aggressiveness, apathy, eating disorders, sleeping disturbances, sphincter disorders. The family's responses may be: denial, overprotection, mothering and hyperactivity in caregiving; c) The relationships with the geriatric institution. They are not always peaceful. Conflicts among patient, family and institution may occur, when the family resents guilt and ambivalence about institutionalisation. A former family caregiver may compete with the institution, because he feels deprived of the caregiving role. So, professional caregivers and geriatricians have to propose a therapeutic plan in which family caregivers are implicated; d) The family-patient pathological relationships. The relationships between family and patient may be pathological, due to the caregiver's psychological pathology. The caregiver may suffer from psychiatric or personality disorders, worsened by the relative's AD. Sometimes, abuse by the family is a danger for the patient; e) The support to the family. Before institutionalisation, family caregiving must be helped and supported by professional caregivers and geriatricians. Some treatments reduce behavioural disorders: cognitive enhancement medication or psychotropic medication. But the most important help is provided by professional care at home, re-education, psychotherapies and, if possible, treatment in a day care centre. In practice, american medical associations have tried to design strategies (with guidelines) to support the family caregiver. After institutionalisation, the family must also be supported, so as to keep a pleasant relationship with the relative. The end-of-life and the death are especially difficult, because the feelings of a person with dementia remain partly misunderstood. And the bereavement of an institutionalised patient seems to be more painful than the bereavement after a long and stressful period of family caregiving.     

Receptors, adenylate cyclase, depression, and lithium

Although numerous studies have suggested that depression may be associated with a reduction in synaptic noradrenaline in the brain, direct beta-adrenergic receptor agonists have not been tested in the treatment of depression until recently. Moreover, newer theories of antidepressant action suggest that a reduction in beta-adrenergic receptor sensitivity is a better correlate of antidepressant treatment than noradrenaline turnover changes. It is possible to evaluate the beta-adrenergic receptor-adenylate cyclase complex in the human periphery by measuring the plasma cyclic AMP rise after adrenergic agonists. A clinical trial of the beta-2 adrenergic agonist salbutamol in depression provided an opportunity to test whether adrenergic receptor subsensitivity does occur during clinical antidepressant treatment. Plasma cyclic AMP before treatment with salbutamol rose 26% in response to salbutamol 0.25 mg iv. After 1 and 3 weeks of oral salbutamol treatment, depression scores declined significantly in 11 depressed patients, while the plasma cyclic AMP response to iv salbutamol declined over 60%. The beta-adrenergic adenylate cyclase remained subsensitive 4 days after cessation of salbutamol therapy. The results support the concept that receptor sensitivity changes occur during human antidepressant therapy. Data are presented that Li, too, markedly reduces activity of beta-adrenergic adenylate cyclase in humans. The effect was evaluated by studying the effect of Li at therapeutic serum concentrations on the plasma cyclic AMP response to subcutaneous epinephrine. The Li effect is specific, since the plasma cyclic AMP response to glucagon is not inhibited. The plasma cyclic GMP response to subcutaneous epinephrine, suggested as a model for presynaptic alpha-noradrenergic mechanisms, is also partially inhibited by Li therapy. Since cyclic AMP and cyclic GMP may be viewed as balancing substances, their interaction may provide a mechanism for Li's dual clinical effects in mania and depression. It is important that in vivo techniques be developed for evaluating receptor changes. The plasma cyclic AMP response to adrenergic stimulation provides an in vivo measure of receptor function that can be useful in studying drug effects during the clinical treatment of humans.     

Fasciitis, perimyositis, myositis, polymyositis, and eosinophilia

Several groups of cases of fasciitis and myositis with eosinophilia are reported. The common features are inflammation into fascia and/or perimysium, and/or muscle fibers; eosinophilia in blood and/or in muscle biopsy. The following classification of 24 cases is suggested: at one end of the spectrum are fasciitis with eosinophilia: diffuse fasciitis (Shulman syndrome): 10 cases (3 with hematological complications); 2 cases of diffuse fasciitis with muscle atrophy; 3 cases of restricted fasciitis. Relapsing perimyositis with eosinophilia belong to the same spectrum, either diffuse (5 cases) with myalgias, or localized (2 cases). Other cases are focal myositis or multiple myositis, polymyositis with eosinophilia. The relationship among these cases is discussed. There is a continuum among the different groups. The pathophysiology remains unknown.     

Delusion, narrative, and affects

Delusions and narrations have very different communicative characteristics. Delusion, when reported, places itself outside of a shared communication, of an interactive field; it is presented as an absolute, non-modifiable, saturated truth, that can only be believed or refuted. A clinical vignette is an example on the possibility that psychoanalytic treatments might be sometime able to at least partly transform a delusion into an account narrated in an interactive situation. The possibility of treatment of a delusion by means of psychotherapy, which deals both with the delusion as a symptom and with the structures underlying it, by creating a relationship whose development can leave the person free to shed his or her delusion, should caution us against too hastily declaring that symptom inaccessible and thus considering it-as not infrequently happens -a sort of "marker" denoting a pathology which, from a psychological perspective, cannot be treated.     

cAMP, tubulin, axonal transport, and regeneration

Mounting a regenerative response after injury is a multistep process for PNS neurons. The reason for failure of mammalian CNS neurons to regenerate successfully may involve more than one of those steps. Han et al. [Exp. Neurol. 189 (2004) 293] and others show that increasing cAMP levels in neuronal cell bodies elicits a partial regenerative response, altering expression of tubulin isotypes but not expression of other growth-associated genes or rate of axonal transport. This approach allows identification of specific steps in the regenerative response and the roles played by these steps.     

Statins, cholesterol, Co-enzyme Q10, and Parkinson's disease

'Statins', drugs that lower cholesterol are widely used. Statins block cholesterol in the body and brain by inhibiting HMG-Co-A reductase. This pathway is shared by CoQ-10. An unintended consequence of the statins is lowering of CoQ-10. As CoQ-10 may play a role in PD, its possible statins may worsen PD. Such a report has appeared. Statins came into wide use in 1997-1998, 6 years before our study began. Thus 74% of our patients on a statin had a PD duration of 1-6 years versus 56% of our patients not on a statin. A direct comparison of patients on a statin and not on a statin would bias the study in favor of the statins: patients on a statin would have a shorter disease duration and less advanced PD. Therefore we divided the patients into two groups. Group I consisted of 128 patients on a statin, and 252 not on a statin who had PD for 1-6 years. In this group, disease severity (Hoehn & Yahr Stage), levodopa dose, Co-enzyme Q10 use, prevalence of 'wearing off', dyskinesia and dementia were similar. Group II consisted of 45 patients on a statin and 200 patients not on a statin who had PD for 7-22 years. In this group disease severity, levodopa dose, Co-enzyme Q10 use, prevalence of wearing off, dyskinesia and dementia were similar. Statins although they may affect Co-enzyme Q10 levels in the body and the brain, do not worsen PD at least as assessed by stage, and prevalence of wearing-off, dyskinesia, and dementia.     

Counterfactuals, Computation, and Consciousness

Using a specially designed cellular automaton capable of emulating completely the function of a human brain, we explore ways in which counterfactual sensitivity, that is, the ability of a computational system to respond to any valid inputs, relates to discrete-state machine consciousness. In this computational framework, the distinction between a computation and the recording of a computation can be blurred arbitrarily, yet the physical implementation of the computation itself is unchanged. From this, we conclude that a purely computational account of consciousness is unsatisfactory.     

Koro,Susto, Windigo

The relational turn in psychoanalysis brought into the foreground the interactive engagement between analyst and patient as a cocreated bidirectional process. It has developed a theory of dissociation and focused our attention on the ways in which multiple self-parts or self-states within each person interact. The author's perspective also emphasizes the importance of rupture and repair in the building of a new attachment relationship, as first theorized in the mother-infant relation. Depicting enactments as part of a necessary process of encountering otherwise inaccessible self-states and the relations they presume, this perspective allows for more “messiness” and what Stern has called an attitude of “courting surprise.” It includes the proposition that such enactment can produce change through new experiences of lawfulness and recognition of feelings and intentions in an attachment relationship.     

Mental illness, neuropsychologic deficits, child abuse, and violence

This review of the psychiatric, neuropsychological, and familial contributions to aggressive behavior makes clear that conduct disorder is not a single diagnostic entity. It is, rather, the final common pathway of the interaction among a variety of different kinds of intrinsic vulnerabilities and environmental stressors. In every aggressive child all of these vulnerabilities (none of which necessarily meets full criteria for a specific DSM-IV diagnosis) and stressors must be considered and, if present, addressed systematically. We know that psychotic symptomatology, especially paranoia, combined with neuropsychological vulnerabilities and a history of severe abuse become a recipe for violence, and the more impaired the child, if abused, the more violent the child will become as an adolescent and adult. The clinician must, therefore, think of himself or herself as the only knowledgeable adult who will ever take the time to discover these ingredients and deal with the violent child positively and therapeutically.     

Hopelessness,depression, substance disorder,and suicidality

Abstract. Background: Most earlier studies of hopelessness as a risk factor for suicidal behavior were based on either clinical or restricted samples. Using a longitudinal study design with a community sample of more than 3,000 participants, we aimed to examine if hopelessness was a long-term predictor of suicidal behaviors. Methods: Using longitudinal data from the Baltimore Epidemiologic Catchment Area (ECA) Program, we assessed the association of hopelessness at baseline and incident suicidal behaviors in the 13-year follow-up period, adjusting for the presence of depression and substance use disorders. Suicide behaviors studied included completed suicide, self-reported attempted suicide, and suicide ideation. Results: Hopelessness was predictive of all three types of suicidal behaviors in the follow-up period, even after adjustment. Persons who expressed hopelessness in 1981 were 11.2 times as likely to have completed suicide over the 13-year follow-up interval (95% confidence interval [1.8, 69.1]). The association between suicidality and hopelessness was stronger and more stable than the association of suicidality with the presence of depression and substance use disorders. Conclusion: Hopelessness was an independent risk factor for completed suicide, suicide attempts, and suicidal ideation. Intervention strategies that lower hopelessness may be effective for suicide prevention.Dr. Kuo is currently with Medical and Health Research Association (MHRA) and National Development and Research Institute, Inc (NDRI), New York, NY, USA. Dr. Gallo is currently with the Department of Family Practice and Community Medicine, University of Pennsylvania, Philadelphia, PA, USA.