Review of withdrawal catatonia: what does this reveal about clozapine?

Withdrawal symptoms are common upon discontinuation of psychiatric medications. Catatonia, a neuropsychiatric condition proposed to be associated with gamma-aminobutyric acid (GABA) hypoactivity due to its robust response to benzodiazepines, has been described as a withdrawal syndrome in case reports but is not a well-recognized phenomenon. The authors undertook a review of withdrawal catatonia with an aim to understand its presentation as well as the medications and psychoactive substances it is associated with. The review identified 55 cases of withdrawal catatonia, the majority of which occurred upon discontinuation of benzodiazepines (24 cases) and discontinuation of clozapine (20 cases). No other antipsychotic medications were identified as having been associated with the onset of a catatonic episode within 2 weeks following their discontinuation. Increasing GABA activity and resultant GABA receptor adaptations with prolonged use is postulated as a shared pharmacological mechanism between clozapine and benzodiazepines that underlie their association with withdrawal catatonia. The existing evidence for clozapine's activity on the GABA system is reviewed. The clinical presentations of benzodiazepine withdrawal catatonia and clozapine withdrawal catatonia appear to differ and reasons for this are explored. One reason is that benzodiazepines act directly on GABAA receptors as allosteric agonists, while clozapine has more complex and indirect interactions, primarily through effects on receptors located on GABA interneurons. Another possible reason for the difference in clinical presentation is that clozapine withdrawal catatonia may also involve receptor adaptations in non-GABA receptors such as dopamine and acetylcholine. The findings from our review have implications for the treatment of withdrawal catatonia, and treatment recommendations are provided. Further research understanding the uniqueness of clozapine withdrawal catatonia among antipsychotic medication may give some insight as to clozapine's differential mechanism of action.

Brain translocator protein occupancy by ONO-2952 in healthy adults: A Phase 1 PET study using [11 C]PBR28.

ONO-2952, a novel antagonist of translocator protein 18 kDa (TSPO), binds with high affinity to TSPO in rat brain and human tumor cell line membrane preparations. This study used the TSPO-specific PET radioligand [11 C]PBR28 to confirm binding of ONO-2952 to brain TSPO in human subjects, and evaluate brain TSPO occupancy and its relationship with ONO-2952 plasma concentration. Sixteen healthy subjects received a single oral dose of 200, 60, 20, or 6 mg ONO-2952 (n = 4 per dose). Two PET scans with [11 C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO-2952 administration. [11 C]PBR28 regional distribution volume (VT ) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (VND ) was obtained on an individual basis for each subject using linear regression as the x-intercept of the Lassen plot. The binding potential relative to VND (BPND ) was derived as the difference between VT in the ROI (VT ROI) and VND , normalized to VND ; BPND = (VT ROI - VND )/VND . TSPO occupancy was calculated as the change in BPND (ΔBPND ) from individual's baseline scan to the on-medication scan to the baseline BPND value. TSPO occupancy by ONO-2952 was dose dependent between 20-200 mg, approaching saturation at 200 mg both in the whole brain and in 15 anatomic regions of interest (ROI). Estimated Ki values ranged from 24.1 to 72.2 nM. This open-label, single-center, single-dose study demonstrated engagement of ONO-2952 to brain TSPO. The relationship between pharmacokinetics and TSPO occupancy observed in this study support the hypothesis that ONO-2952 could potentially modulate neurosteroid production by binding to brain TSPO.

[Silexan and narcosis : case report and possibilities of preoperative and perioperative management]. / Silexan und Narkose : Fallbericht und Möglichkeiten des prä- sowie perioperativen Managements.

The increased use of phytotherapeutic drugs means that anesthetists are more often confronted with these drugs. In this case report possible problems which can occur are demonstrated exemplified by silexan. Silexan is a phytotherapeutic anxiolytic which is used in anxiety disorders. Because of its potential mechanism of action via the neurotransmitter gamma-aminobutyric acid (GABA) receptors interactions with narcotic drugs are possible. The case of an 18-year-old girl who underwent an operation under general anesthesia while taking silexan as long-term medication is presented. The desired depth of narcosis could only be reached by inhalative induction with sevoflurane after unsuccessful induction attempts using intravenous propofol and thiopental. Possible explanations for this route and inhalative induction as a possible alternative are discussed.

Exploring off-targets and off-systems for adverse drug reactions via chemical-protein interactome--clozapine-induced agranulocytosis as a case study.

In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs.

Dose-dependent protective effect of connexin43 mimetic peptide against neurodegeneration in an ex vivo model of epileptiform lesion.

Epileptic seizures typically result in delayed neuronal loss secondary to the initial damage and an up-regulation in connexin43 (Cx43). This study investigated the role of Cx43 gap junctions in lesion spread and cell loss following epileptiform activity. Epileptiform injury in hippocampal slice cultures was induced by 48 h exposure to 100 µM bicuculline methochloride (BMC). During the 24h recovery period following BMC treatment, lesion spread was observed in the CA1. A Cx43 mimetic peptide, applied during either the BMC treatment or recovery periods, produced concentration- and exposure time-dependent neuroprotection, as measured by propidium iodide uptake at the end of the recovery period. During the BMC period, peptide concentrations between 5 and 50 µM (sufficient to block hemichannels) had a protective effect while a substantial gap junction blockade with 500 µM peptide exacerbated the lesion. By contrast, all doses applied during the recovery period protected the CA1 region from further damage. The results indicate that while the slices are undergoing excessive neuronal firing and epileptic stress, gap junction communication appears to be essential for tissue survival but hemichannel opening may be damaging. Following epileptiform insult, however, gap junction communication plays a crucial role in the spread of neuronal damage. The findings from this study identify gap junction communication as a potential therapeutic target for epilepsy.

Inhibitory effects of amiloride on the current mediated by native GABA(A) receptors in cultured neurons of rat inferior colliculus.

1. The diuretic amiloride is known to modulate the activity of several types of ion channels and membrane receptors in addition to its inhibitory effects on many ion transport systems. However, the effects of amiloride on some important ion channels and receptors, such as GABA(A) receptors, in the central nervous system have not been characterized. 2. In the present study, we investigated the functional action of amiloride on native GABA(A) receptors in cultured neurons of rat inferior colliculus using whole-cell patch-clamp recordings. 3. Amiloride reversibly inhibited the amplitude of the GABA-induced current (I(GABA)) in a concentration-dependent manner (IC(50) 454 +/- 24 micromol/L) under conditions of voltage-clamp with a holding potential at -60 mV. The inhibition depended on drug application mode and was independent of membrane potential. Amiloride did not change the reversal potential of I(GABA). Moreover, amiloride induced a parallel right-ward shift in the concentration-response curve for I(GABA) without altering the maximal value and Hill coefficient. 4. The present study shows that amiloride competitively inhibits the current mediated by native GABA(A) receptors in the brain region, probably via a direct action on GABA-binding sites on the receptor. The findings suggest that the functional actions of amiloride on GABA(A) receptors may result in possible side-effects on the central nervous system in the case of direct application of this drug into the cerebrospinal fluid for treatment of diseases such as brain tumours.

Visualizing localized dynamic changes during epileptic seizure onset in vivo with diffuse optical tomography.

Diffuse optical tomography (DOT) is a promising functional imaging modality due to its ability to provide quantitative and dynamic tomographic imaging of brain functions. This pilot study was conducted to demonstrate that DOT can be used to visualize the changes in local hemodynamics during seizures. The focal seizure was induced by microinjection of 10 microl of 1.9 mM GABAA antagonist bicuculline methiodide (BMI) into the left parietal neocortex of male Harlen Sprague-Dawley rats, which was imaged by a multispectral continuous-wave DOT system. Functional images were obtained by our finite element based image reconstruction algorithm. A series of dynamic 2D images were obtained to delineate the time course of concentration changes of oxyhaemoglobin, deoxyhaemoglobin, and total hemoglobin in the rat brain during seizure onset. The BMI induced epileptic foci were localized and observed over time from the images obtained. Our results suggest that diffuse optical tomography may be a promising modality for epilepsy imaging due to its ability to localize epileptic foci as well as its potential to map the functional activity in the area of human cerebral cortex in planning of epilepsy surgery.

Reproductive health effects and teratogenicity of antiepileptic drugs.

Women with epilepsy are less likely to bear children than women in the general population, and although this reduced fertility can be attributed in part to effects of the disease itself, the effects of antiepileptic drugs (AEDs), including changes in reproductive endocrine function, are also a factor. Conversely, some AEDs interact with oral contraceptives and can increase the risk for contraceptive failure and unplanned pregnancy. Women with epilepsy also have elevated rates of congenital anomalies and major malformations in their offspring, for which exposure of the developing fetus to AEDs taken by the mother appears to be responsible. In utero exposure to some AEDs may also be associated with increased risk for impaired cognitive function in the growing child. Clearly, possible long-term effects on reproductive health and pregnancy outcomes require careful attention when AED therapy is being considered for a patient with childbearing potential. Moreover, because AEDs are increasingly being used in therapy for other conditions such as migraine, bipolar disorder, and pain, it is not only the treatment of women with epilepsy that will be affected by these concerns.

Malignant McLeod myopathy.

Mild myopathy is a common manifestation of the X-linked McLeod neuroacanthocytosis syndrome. We present a patient with McLeod syndrome and a primarily subclinical myopathy, who developed severe rhabdomyolysis with renal insufficiency after a prolonged period of excessive motor restlessness due to an agitated psychotic state and a single dose of clozapine. Other possible causes for rhabdomyolysis such as prolonged immobility, trauma, hyperthermia, generalized seizures, toxin exposure, or metabolic changes were excluded. Clinical course was favorable, with persistent slight elevation of serum creatine kinase levels caused by the underlying myopathy. Our findings suggest that McLeod myopathy is a predisposing factor for severe rhabdomyolysis. This possibly life-threatening condition should be added to the clinical spectrum of McLeod syndrome, and serum creatine kinase levels should be carefully monitored in patients with this syndrome, particularly if a hyperkinetic movement disorder is present or neuroleptic medication is used.

Sex difference in susceptibility to epileptic seizures in rats: importance of estrous cycle.

Sex difference in seizure susceptibility is one of the unresolved issues of epilepsy. It is known that estrogen is excitatory and progesterone is inhibitory to the central nervous system. Therefore, it is to be expected that seizure susceptibility may be associated with the estrous cycle, which should be tested in epilepsy research. Otherwise, different results in epilepsy studies could be an artifact of the estrous cycle. Reports in the literature are inconsistent about testosterone effects on seizures. In light of these considerations, sex differences in seizure susceptibility were restudied in rats. There was no significant sex difference in mean latencies to picrotoxin-induced seizures; prestrous-females had the shortest latencies to epileptic seizures compared to males and estrousfemales. With testosterone-injected rats, there was either no sex difference in latencies (to akinetic and focal seizures) or females had significantly shorter latencies than males (to status epilepticus, generalized tonic-clonic seizures, and myoclonic seizures). Testosterone-treated male rats had a significantly longer mean latency than controls for status epilepticus only; otherwise, these males showed no significant differences between mean latencies before and after testosterone (to focal, myoclonic, or generalized tonic-clonic seizures). In females, mean latencies to myoclonic seizures and status epilepticus were significantly shorter after testosterone than before. It was concluded that there is a sex difference in susceptibility to epileptic seizures in rats, provided that the estrous cycle is taken into account. Testosterone may increase and decrease seizure susceptibility in females and males, respectively. These effects may be important for understanding the mechanisms of epileptic phenomena and may provide some important clues to epilepsy treatment.