Biomedical subjects

Shitij Kapur

Publications and source records attributed to Shitij Kapur.

At least 37 records · Page 2Linked to original sources

PubMed2006

In vivo characterization of the pharmacokinetics and pharmacological properties of [11C]-(+)-PHNO in rats using an intracerebral beta-sensitive system.

This study reports on the binding kinetics and pharmacological characterization of [11C]-(+)-PHNO ((+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol), a promising agonist radiotracer for in vivo evaluation of the D2-receptor. Its in vivo kinetics were monitored in rat striatum and cerebellum using a beta-sensitive Microprobe system. Control studies showed that [11C]-(+)-PHNO binding was reversible and reached a peak time equilibrium of specific binding in striatum 30 min after radiotracer injection. The binding potential (BP) calculated by the simplified reference tissue model was 3-fold higher than that measured with [11C]-(-)-NPA (2.14 +/- 0.50 vs. 0.66 +/- 0.01, respectively). In contrast, the methyl analog of (+)-PHNO, [11C]-(+)-MHNO, which displayed promising D2-agonist properties in vitro, showed no specific binding in the striatum in vivo. [11C]-(+)-PHNO binding was totally blocked by raclopride (1 mg/kg; i.v.) and 97% displaced by NPA (2 mg/kg; i.v.) suggesting that [11C]-(+)-PHNO was specific for the high affinity states of D2/D3-receptors. However, (+)-PHNO (1 mg/kg; i.v.) totally blocked and displaced [11C]-raclopride binding in striatum. Thus, (+)-PHNO at high concentrations might be able to bind to the low affinity states of D2/D3-receptors. After an amphetamine pretreatment (2 mg/kg; i.v.), a 69% decrease in BP value (P < 0.05) was observed for [11C]-(+)-PHNO indicating that its binding was highly sensitive to variations of endogenous DA. These results substantiate the use of [11C]-(+)-PHNO as an agonist radiotracer for D2-imaging. The sensitivity of its binding to competition with endogenous DA suggests an association with the subset of high affinity state D2-receptors.

Amphetamine↗

PubMed2006

How antipsychotics work-from receptors to reality.

How does a small molecule blocking a few receptors change a patients' passionately held paranoid belief that the FBI is out to get him? To address this central puzzle of antipsychotic action, we review a framework linking dopamine neurochemistry to psychosis, and then link this framework to the mechanism of action of antipsychotics. Normal dopamine transmission has a role in predicting novel rewards and in marking and responding to motivationally salient stimuli. Abnormal dopamine transmission alters these processes and results in an aberrant sense of novelty and inappropriate assignment of salience leading to the experience of psychosis. Antipsychotics improve psychosis by diminishing this abnormal transmission by blocking the dopamine D2/3 receptor (not D1 or D4), and although several brain regions may be involved, it is suggested that the ventral striatal regions (analog of the nucleus accumbens in animals) may have a particularly critical role. Contrary to popular belief, the antipsychotic effect is not delayed in its onset, but starts within the first few days. There is more improvement in the first 2 weeks, than in any subsequent 2-week period thereafter. However, a simple organic molecule cannot target the complex phenomenology of the individual psychotic experience. Antipsychotics diminish dopamine transmission and thereby dampen the salience of the pre-occupying symptoms. Therefore, in the initial stage of an antipsychotic response, the patients experience a detachment from symptoms, a relegation of the delusions and hallucinations to the back of their minds, rather than a complete erasure of the symptoms. Only with time, and only in some, via the mediation of new learning and plasticity, is there a complete resolution of symptoms. The implications of these findings for clinical care, animal models, future target discovery and drug development are discussed.

Animals↗

PubMed2006

Dopamine, prediction error and associative learning: a model-based account.

The notion of prediction error has established itself at the heart of formal models of animal learning and current hypotheses of dopamine function. Several interpretations of prediction error have been offered, including the model-free reinforcement learning method known as temporal difference learning (TD), and the important Rescorla-Wagner (RW) learning rule. Here, we present a model-based adaptation of these ideas that provides a good account of empirical data pertaining to dopamine neuron firing patterns and associative learning paradigms such as latent inhibition, Kamin blocking and overshadowing. Our departure from model-free reinforcement learning also offers: 1) a parsimonious distinction between tonic and phasic dopamine functions; 2) a potential generalization of the role of phasic dopamine from valence-dependent "reward" processing to valence-independent "salience" processing; 3) an explanation for the selectivity of certain dopamine manipulations on motivation for distal rewards; and 4) a plausible link between formal notions of prediction error and accounts of disturbances of thought in schizophrenia (in which dopamine dysfunction is strongly implicated). The model distinguishes itself from existing accounts by offering novel predictions pertaining to the firing of dopamine neurons in various untested behavioral scenarios.

Action Potentials↗

PubMed2006

A PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone.

OBJECTIVE: Long-acting injectable risperidone represents the first clinically available depot atypical antipsychotic. The present study used positron emission tomography (PET) to evaluate its dopamine D(2) binding profile at doses of 25, 50, or 75 mg administered every 2 weeks. METHOD: After achieving stabilization with one of the doses, nine patients with a diagnosis of schizophrenia or schizoaffective disorder underwent [(11)C]raclopride PET to measure D(2) occupancy. Participants were scanned twice during the 2-week injection interval: within 3 days after injection (postinjection) and within 5 days before the next injection (preinjection). At the same time, plasma was collected for measurements of risperidone plus 9-hydroxyrisperidone. RESULTS: Mean post- and preinjection D(2) occupancy levels for the 25-, 50-, and 75-mg doses were 71.0% and 54.0%, 74.4% and 65.4%, and 81.5% and 75.0%, respectively. There was a significant correlation between dose and plasma concentrations of risperidone plus 9-hydroxyrisperidone, and the estimated plasma concentration associated with 50% D(2) occupancy (ED(50)) was 11.06 ng/ml. Prolactin levels were not correlated with drug levels or D(2) occupancy. CONCLUSIONS: All three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal symptoms. Doses of 25 or 50 mg should provide therapeutic efficacy while minimizing the risk of extrapyramidal symptoms.

Adult↗

PubMed2006

The "delayed onset" of antipsychotic action--an idea whose time has come and gone.

For years, it has been known that the "onset" of the antipsychotic response is "delayed," and this notion is expressed in many major textbooks, informs clinical decisions and has even led to the search for biological markers responsible for this delayed onset. But is the onset of antipsychotic action really delayed? In this review, we bring together data from several recent studies of antipsychotic drugs that show that the onset of the antipsychotic effect is within the first day; the effect is distinguishable from behavioural sedation; is specific to antipsychotic drugs; is seen with oral and parenteral preparations; and is seen with typical and atypical antipsychotics. More anti- "psychotic" improvement is seen within the first 2 weeks than in any other 2-week period thereafter, and more improvement is seen in the first month than in the rest of the year of follow-up. This body of data convincingly refutes the notion of "delay" in the onset of antipsychotic action and suggests an "early" onset instead. The implications of this finding for clinical decision-making, mechanisms of antipsychotic action and drug discovery are discussed.

Antipsychotic Agents↗

PubMed2005

High-affinity states of human brain dopamine D2/3 receptors imaged by the agonist [11C]-(+)-PHNO.

BACKGROUND: The high-affinity states of dopamine D2-receptors (D2(high)) are postulated to be functionally responsible for signal transduction. At present, no useful in vivo method exists to selectively measure D2(high) in humans, as current D2 radioligands for positron emission tomography (PET) are either not D2-selective or do not differentiate between D2 high- and low-affinity states. METHODS: The D2-agonist (+)-PHNO [(+)4-propyl-9-hydroxynaphthoxazine] was labeled with carbon-11 and studied with PET. Eight [11C]-(+)-PHNO scans were acquired in four healthy volunteers. RESULTS: We observed greatest [11C]-(+)-PHNO accumulation in caudate, putamen, and globus pallidus [binding potentials (BPs): 3.00 +/- .4, 3.10 +/- .2, and 4.17 +/- 1.2]. Small but detectable binding was identified in the substantia nigra/ventral tegmental area. Preliminary test-retest data in two subjects suggests BP-estimates to be reliable. Pre-treatment with haloperidol reduced BPs in regions showing specific binding with no detectable changes in cerebellum. Parallel imaging with [11C]-raclopride showed substantial differences in the globus pallidus. CONCLUSIONS: [11C]-(+)-PHNO proved to be a D2/3-receptor agonist-radioligand with good brain uptake and favorable kinetics for PET in humans. [11C]-(+)-PHNO delineated D2/3-receptor rich brain regions with high signal-to-noise ratio. This is the first demonstration of a viable agonist-radioligand for D2 receptors in humans and opens the door for investigating D2(high) in health and disease.

Adult↗

PubMed2005

Dissociation between in vivo occupancy and functional antagonism of dopamine D2 receptors: comparing aripiprazole to other antipsychotics in animal models.

The novel antipsychotic aripiprazole requires high (>90%) striatal D2 receptor occupancy (D2RO) to be clinically active, but despite its high D2RO it does not show extrapyramidal symptoms. While most antipsychotics are active at nearly 65% D2RO, they show motor side effects when D2RO exceeds 80%. We investigated this discrepancy between D2RO, 5HT2 receptor occupancy (5-HT2RO) and in vivo functional activity of aripiprazole in comparison to haloperidol (typical) and risperidone (atypical) in animal models. All three drugs showed dose-dependent D2RO. While risperidone clearly showed higher 5-HT2RO than D2RO, aripiprazole and haloperidol showed higher D2RO than 5-HT2RO at all doses. Haloperidol and risperidone induced catalepsy at doses producing >80% D2RO, while aripiprazole despite higher D2RO (>90%) induced no catalepsy. Haloperidol and risperidone's ED50 values for inhibition of conditioned avoidance response (CAR) and amphetamine-induced locomotor activity (AIL) corresponded to approximately 60% D2RO. In contrast, aripiprazole showed a significant dissociation; while it blocked AIL at similar D2RO, a 23-fold higher dose (86% D2RO) was required to inhibit CAR. FOS expression in shell region of the nucleus accumbens was significant for all drugs at D2ROs that were effective in CAR. However, in the core region of the nucleus accumbens and dorsolateral striatum, aripiprazole differed from the others in that despite high D2RO it induced low FOS. Haloperidol and risperidone showed dose/occupancy-dependent prolactin elevations, while aripiprazole did not. Across models, haloperidol and risperidone show similar occupancy-functional antagonism of the D2 system, while aripiprazole shows a clear dissociation. Partial agonism of aripiprazole offers a good explanation for this dissociation and provides a framework for understanding occupancy-functional relationships of partial D2 agonist antipsychotics.

Animals↗

PubMed2005

Sensitization to amphetamine, but not PCP, impairs attentional set shifting: reversal by a D1 receptor agonist injected into the medial prefrontal cortex.

RATIONALE: Repeated exposure to psychomotor stimulants can lead to sensitization to their effects, and sensitization has been implicated in the pathophysiology of schizophrenia and drug abuse. These disorders are characterized by cognitive deficits, particularly in prefrontally mediated executive function. OBJECTIVE: The present experiments were conducted to investigate the effects of sensitizing regimens of amphetamine and phencyclidine (PCP) on attentional set shifting. METHODS: Rats received injections of amphetamine, PCP or saline three times per week for 5 weeks. Four weeks later, rats were trained to dig for food in one of two bowls, each bowl having an odour and a texture. Only one dimension (odour or texture) correctly predicted which bowl was baited. Rats were then tested on a series of discriminations including those requiring an intra-dimensional shift (IDS), an extra-dimensional shift (EDS) or a reversal of previously relevant and irrelevant stimuli. RESULTS: Rats sensitized to amphetamine performed normally on the IDS, but were impaired on the EDS, as well as on reversal discriminations. PCP-sensitized rats were unaffected on any of the discriminations. In amphetamine-sensitized rats the deficit at the EDS stage was reversed by infusion of the D(1) receptor agonist SKF38393 into the medial prefrontal cortex (mPFC). CONCLUSIONS: Results show that the amphetamine-sensitized state impairs prefrontally mediated attentional set shifting. This is consistent with cognitive deficits in schizophrenia and addiction, and with the evidence that amphetamine sensitization is accompanied by functional changes in the mPFC. These results further add to a growing literature showing that activating D(1) receptors in the mPFC improves aspects of cognition.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2005

From dopamine to salience to psychosis--linking biology, pharmacology and phenomenology of psychosis.

How does an excess in a neurochemical lead someone to being paranoid about the intentions of their neighbour? And why does blocking a dopamine receptor improve this symptom? In this article we present a heuristic framework which attempts to link the biology, phenomenology and pharmacology of psychosis. Focussing on dopamine's role in reward prediction and motivational salience we propose that psychosis arises from an aberrant assignment of novelty and salience to objects and associations. Antipsychotics block dopamine receptors and decrease dopamine transmission, which leads to the attenuation of aberrant novelty and salience. This 'salience' framework accounts for existing data and questions several current assumptions about the speed of onset phenomenological effects of antipsychotics and their behavioral effects in animal models. We review new data to show that in contrast to the prevailing idea of a "delayed onset" of antipsychotic action, the improvement is evident in the first few days. Antipsychotics do not eradicate symptoms, but create a state of "detachment" from them. And the actions of antipsychotics in the conditioned avoidance response model, one of the best established animal models for identifying antipsychotic action, are consistent with the idea that they dampen aberrant as well as normal motivational salience. The article discusses the caveats, limitations as well as the clinical implications of the salience framework.

Antipsychotic Agents↗

PubMed2005

Effects of novel antipsychotics, amisulpiride and aripiprazole, on maternal behavior in rats.

RATIONALE: Rat maternal behavior, which entails complex motivational and social factors, is disrupted by the currently available typical and atypical antipsychotics. It is thought that this disruption reflects a side effect of antipsychotics, modeling the neuroleptic-induced negative or deficit state. Amisulpiride and aripiprazole are new atypical antipsychotics with mechanisms of action distinct from the current typical and atypical antipsychotics. The effects of these drugs on maternal behavior have not been explored. OBJECTIVE: In the present study, we systematically examined the behavioral effects of amisulpiride and aripiprazole on maternal behavior in postpartum female rats. METHODS: Various components of maternal behavior (pup retrieval, pup licking, nest building and pup nursing) were examined repeatedly over a period of 24 h after a single injection of three doses of amisulpiride (10, 30, and 100 mg/kg s.c.) and aripiprazole (3, 10, and 30 mg/kg). RESULTS: Amisulpiride at the lower doses (10 and 30 mg/kg) enhanced pup licking, and only at the highest dose disrupted the active components of maternal behavior such as pup retrieval and nest building. Its effect was delayed in onset and prolonged as compared to other antipsychotics. Aripiprazole, even at the highest dose (30 mg/kg) did not impair pup retrieval or pup licking. However, it did disrupt nest building and led to enhanced pup nursing. CONCLUSIONS: The unique effects of these two drugs may be due to their unique actions at the mesolimbic dopamine synapses. The sparing of the major components of maternal behavior by aripiprazole may be related to its partial agonist effects, whereas the enhancement of pup licking by amisulpiride may be related to its dose-dependent preferential effect on the presynaptic autoreceptors. The potential clinical implications of these findings are discussed.

Amisulpride↗

PubMed2005

Contrasting loxapine to its isomer isoloxapine--the critical role of in vivo D2 blockade in determining atypicality.

BACKGROUND: Loxapine is a typical antipsychotic while isoloxapine, its 8Cl-isomer, shows atypicality in some animal models. The basis for this difference is not well understood. The purpose of this study was to systematically compare the two drugs in in vitro and in vivo animal models, and to understand mechanisms underlying their differential typical/atypical profiles. METHODS: The in vitro and in vivo receptor profiles as well as the action of loxapine and isoloxapine on rat conditioned avoidance response (CAR), catalepsy (CAT), striatal FOS expression and prolactin levels were determined. To understand loxapine's typical profile, we added MDL100,907, to provide loxapine+MDL the same in vivo 5-HT2/D2 ratio as isoloxapine, while holding its D2 component constant. RESULTS: Isoloxapine behaved as an "atypical" antipsychotic demonstrating CAR inhibition, low CAT, no significant prolactin elevation, and minimal FOS expression in the dorsolateral striatum. Loxapine behaved like a typical antipsychotic, showing unexpectedly high in vivo D2 occupancy. Addition of MDL100,907, which resulted in a very high 5-HT2/D2 in vivo ratio, did not alter loxapine + MDL's typical profile. CONCLUSIONS: Loxapine's behaviour as a typical antipsychotic is most likely due to its disproportionately high D2 occupancy. Appropriate action at D2 receptors in vivo, rather than the high 5-HT2/D2 ratio, seems to be critical in determining why isoloxapine behaves like an atypical antipsychotic.

Animals↗

PubMed2005

Radiosynthesis and evaluation of [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography.

In vivo imaging of dopamine D2 receptors with agonist (as opposed to the more commonly employed antagonist) radiotracers could provide important information on the high-affinity (functional) state of the D2 receptor in illnesses such as schizophrenia, movement disorders, and addictions. We report here the radiosynthesis and evaluation of the potent D2 agonist (+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol, (+)-3, labeled with carbon-11, as a potential radiotracer for imaging the high-affinity state of dopamine D2 receptors with positron emission tomography (PET). [(11)C]-(+)-3 was reliably synthesized in the quantities and at the specific activities and radiochemical purities required for human PET studies. Ex vivo biodistribution studies in rat brain demonstrated that [(11)C]-(+)-3 crossed the blood-brain barrier readily and had an appropriate regional brain distribution for a radiotracer that maps dopamine D2 receptors. The binding of [(11)C]-(+)-3 was saturable and demonstrated an excellent signal-to-noise ratio as measured by its striatum-to-cerebellum ratio of 5.6, 60 min postinjection. The binding was highly stereospecific, and blocking and displacement studies were consistent with selective and specific binding to the dopamine D2 receptors. Further, [(11)C]-(+)-3 showed marked and appropriate sensitivity to both increases and decreases in the levels of endogenous dopamine. Brain radioactive metabolite and physicochemical measurements are in full accord with the desired properties of a neuroreceptor imaging agent for PET. All of the above, coupled with the documented full D2 agonistic properties of (+)-3, strongly indicate that [(11)C]-(+)-3 is a leading candidate radiotracer for the imaging of the dopamine D2 high-affinity state using PET in human subjects.

Animals↗

PubMed2005

Effects of chronic typical and atypical antipsychotic drug treatment on maternal behavior in rats.

Understanding the effects of antipsychotics on maternal behavior is important for understanding the poor quality of mother-infant interaction in schizophrenia. Previous preclinical work has demonstrated that acute treatment with typical and atypical antipsychotics disrupts maternal behavior. However, the effects of chronic antipsychotic treatment on maternal behavior are unknown. This issue is of importance since clinical use of antipsychotic medication requires continuous exposure to these drugs. In this study, we treated postpartum rats with haloperidol (0.25 mg/kg/day) or olanzapine (7.5 mg/kg/day), via osmotic minipumps or daily injections for 3 weeks. Maternal behavior was assessed every third day. On each observation day, maternal behavior was observed twice, once just prior to the daily injection ("trough" as this was 24 h after last injection) and again 2 h after the injection ("peak"). Daily injections of haloperidol and olanzapine significantly disrupted pup retrieval, pup licking, nest building at peak, but this effect was gone by trough. Drug administration via minipumps also disrupted these behaviors, but the effects were less severe. Pup nursing was enhanced by either method of drug administration. No evidence of sensitization or tolerance associated with chronic drug treatment was found. It is concluded that chronic antipsychotic treatment disrupts active maternal behaviors and this disruption, most likely to lead to side effects in humans, should be avoided in future drug development.

Animals↗

PubMed2005

Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs.

Neurogenesis has been implicated in antidepressant drug action and animal models of depression, suggesting that proliferating cells play a role in psychiatric disorders. Similar studies using antipsychotic drugs have yielded conflicting results, perhaps because of the lack of focus on specific cell types. We examine the effect of haloperidol on neural stem cells (NSCs), the ultimate precursors for adult cell genesis. We show that haloperidol increases NSC numbers, resulting in more progenitors and more new neurons and glia in the adult rat brain. The increase in NSCs by haloperidol is dependent on central dopamine D2 receptors, and these receptors are expressed by NSCs. D2 receptor stimulation in vitro inhibits NSC proliferation, which is reversed by haloperidol. Thus, haloperidol increases adult mammalian brain proliferation by antagonizing dopamine at D2 receptors on NSCs. These findings demonstrate a direct link between neural activity and NSC proliferation and implicate cell genesis in antipsychotic drug effects.

Animals↗

PubMed2005

Sensitization to amphetamine, but not phencyclidine, disrupts prepulse inhibition and latent inhibition.

RATIONALE: Schizophrenia has been linked to dysregulation of dopamine and glutamate transmitter systems. Attempts to model aspects of schizophrenia in animals have made use of treatments that primarily affect dopaminergic (e.g., amphetamine, Amp) and glutamatergic (e.g., phencyclidine, PCP) function. In addition to exerting short-term acute effects, these agents also induce long-term effects, as seen, for example, in neurochemical and behavioural sensitization. OBJECTIVES: The goal of this work was to compare Amp- and PCP-sensitized states on two measures of information processing that are impaired in schizophrenia, prepulse inhibition (PPI) of the acoustic startle reflex and latent inhibition (LI). METHODS: Rats received injections of Amp, PCP or saline 3 days per week for 3 weeks. The Amp dose increased from 1 to 3 mg/kg, at the rate of 1 mg/kg each week. The PCP dose was 3 mg/kg throughout. After various periods of withdrawal rats were tested for PPI and LI. RESULTS: Repeated intermittent treatment with Amp or PCP resulted in augmented locomotor responses to challenge with each drug, providing an operational index that sensitization had occurred. Rats sensitized to Amp showed disrupted PPI when tested drug free at 3, 21 and 60 days of withdrawal. Amp-sensitized rats also showed abolition of the LI effect. Rats sensitized to PCP did not show deficits in any of these behaviours when tested drug free. CONCLUSIONS: Because disrupted PPI and LI have both been reported in schizophrenic patients, these results suggest that the Amp-sensitized state may represent a useful model for investigating the neural bases of information processing deficits in schizophrenia.

Amphetamine↗

PubMed2005

A putative animal model of the "prodromal" state of schizophrenia.

BACKGROUND: There is growing interest in detecting and treating schizophrenia during the "prodrome," before the symptoms are fully manifested. The objective of this study was to develop a putative model of the prodrome and study the effects of medications on it. METHODS: Rats were treated with different regimens of amphetamine to produce full sensitization (full syndrome) and partial sensitization (to model the prodromal state) and were then treated with typical and atypical antipsychotics and a D1 antagonist to mimic early intervention. After several weeks of withdrawal, locomotor activity in response to amphetamine and behavioral deficits (prepulse inhibition [PPI] and latent inhibition [LI]) were examined. RESULTS: Animals that received the full sensitization showed significant increase in locomotor activity and a disruption in both PPI and LI. Animals treated with a partial regimen showed only a muted phenotype. The animals that received "early intervention" did not show progression from the prodromal to the full-blown phenotype. CONCLUSIONS: The partial regimen of amphetamine injections provided a modified phenotype that could be regarded as a representative of the "prodromal" state. Early intervention, instituted once the prodromal state was already developed, prevented further progression into the full phenotype analogous to schizophrenia.

Amphetamine↗

PubMed2005

Continuous but not intermittent olanzapine infusion induces vacuous chewing movements in rats.

BACKGROUND: Continuous, but not intermittent, infusion with a conventional antipsychotic (haloperidol, HAL) can induce the vacuous chewing movement (VCM) syndrome in rats. The objective of this study was to determine whether continuous, versus intermittent, olanzapine (OLZ) infusion differently affects the development of VCMs. METHODS: Experiment 1: Animals were treated with 7.5 mg/kg/day of OLZ or vehicle (VEH) via either minipump (MP) or daily subcutaneous (SC) injections for 8 weeks. Experiment 2: A separate group of rats were treated with 15 mg/kg/day of OLZ, or 1 mg/kg/day of HAL or VEH via MP for 8 weeks. Dopamine D2 receptor occupancy levels were measured, ex vivo, with [3H]-raclopride. RESULTS: Experiment 1: Rats receiving 7.5 mg/kg/day of OLZ via MP (51% D2 occupancy), but not those receiving the same dose via daily SC injections (94% peak D2 occupancy), showed significant VCM levels compared with control animals (p = .02). Experiment 2: Both OLZ (67% D2 occupancy) and HAL (79% D2 occupancy) led to similar increases in VCMs compared with VEH (p = .005). CONCLUSIONS: This study provides strong evidence that even an atypical antipsychotic like OLZ, which rarely gives rise to tardive dyskinesia in the clinic, can lead to the VCM syndrome in rats if the antipsychotic is administered in a method (via MP) that leads to continuous presence of the drug in the brain.

Analysis of Variance↗

PubMed2005

How antipsychotics work: the patients' perspective.

BACKGROUND: While much is known about the neuropharmacology and objective efficacy of antipsychotics, little is known about how these drugs act on psychosis from the patients' perspective. Most previous studies of the patient's perspective have focused on drug tolerability and acceptability-rather than their effects on psychosis per se. METHODS: The authors examined how antipsychotics work from a patient's perspective by analyzing their responses to a subjective questionnaire. Ninety-one patients with schizophrenia (cross-sectional component) and eight neuroleptic naïve patients (before and after treatment, longitudinal component) participated. The patients' responses to the questionnaire were analyzed using Principal Component Analysis (PCA) and general linear models. RESULTS: Analysis of the patients' responses showed that from their perspective the drugs were substantially more effective in: "help deal, help stop thinking, and make the symptoms not bother" rather than "take away" or "change my mind". This differentiation was clear in the raw data and was supported by a formal PCA. Two underlying factors-the first termed detachment and second eradication-explained 71% of the variance in the patients' perspective on how antipsychotics work for them. Neuroleptic naïve patients, who had no prior exposure, expected drugs to help with both detachment and eradication, but, changed their mind with just 6 weeks of experience with the medications. CONCLUSIONS: From the patients' perspective the action of antipsychotics is best characterized by a detachment from symptoms-rather than an eradication or elimination of symptoms. They have more wide-ranging expectations prior to antipsychotic exposure, but, even 6 weeks of exposure is sufficient to change their mind in favor of detachment. This finding is consistent with some of the very earliest ideas that antipsychotics produced a state of "indifference" and is also consistent with the more recent, neurobiologically informed notions that antipsychotics work by dampening the salience of psychotic symptoms.

Adolescent↗