Biomedical subjects

Steven G Potkin

Publications and source records attributed to Steven G Potkin.

At least 37 records · Page 2Linked to original sources

PubMed2004

Gender: a major determinant of brain response to nicotine.

Biological factors responsible for nicotine initiation and dependence are largely unknown. Men and women smoke differently, and may smoke for different reasons. Brain metabolic response to nicotine may explain gender differences in nicotine use. We used FDG-PET to measure brain metabolic response on placebo and following nicotine administered by patch in 42 females and 77 males (smokers and non-smokers) while performing a Continuous Performance Task (CPT) or the Bushman Competition and Retaliation Task (CRT). Nicotine administration affected brain metabolism much differently in males and females, and these differences were dependent on task and smoking history. In the placebo condition female smokers performing the CPT and female non-smokers performing the CRT consistently had higher brain metabolism than males, especially in the entire prefrontal system and the mid and anterior temporal lobe, language cortices, and related subcortical systems. The overall effect of nicotine was to decrease these gender differences in brain metabolism.

Administration, Cutaneous↗

PubMed2004

Improvement in cognitive function following a switch to ziprasidone from conventional antipsychotics, olanzapine, or risperidone in outpatients with schizophrenia.

OBJECTIVE: To assess changes in cognitive function in stable outpatients with schizophrenia switched to ziprasidone from conventional antipsychotics (n = 108), olanzapine (n = 104), or risperidone (n = 58) because of suboptimal efficacy or poor tolerability. METHODS: In three separate 6-week trials, patients received ziprasidone 40 mg b.i.d. for 2 days, followed by 20-80 mg b.i.d. for the next 40 days. Before switching, and at endpoint, patients were evaluated with tests of working and secondary verbal memory, vigilance, visuomotor speed, verbal fluency, and executive functioning. Principal components factor analysis was performed to test for clustering of cognitive variables. RESULTS: Significant improvements were seen at endpoint in secondary verbal memory (in all three groups), vigilance (in patients switched from conventional antipsychotics or risperidone), executive function (in patients switched from conventional antipsychotics or risperidone), and verbal fluency. Factor analysis on baseline scores suggested reduction of the cognitive variables to three factors: verbal skills, attention and short-term memory, and executive functioning. Analysis of z-transformed mean change in factor scores showed significant improvement in verbal skills and global score following the switch from conventional antipsychotics, olanzapine, or risperidone. CONCLUSIONS: Patients requiring a change in antipsychotic therapy may exhibit cognitive improvement following a switch to ziprasidone.

Adolescent↗

PubMed2004

Hostility differentiates the brain metabolic effects of nicotine.

The brain mechanisms underlying the cause of nicotine dependence are unknown, however, hostility traits are associated with increased susceptibility to nicotine dependence. We used FDG PET to measure brain metabolic response to nicotine administered by patch while the subject performed the Bushman aggression task in 86 high- and low-hostility subjects. Low-hostility trait subjects demonstrated no significant change in brain metabolic response to nicotine. In marked contrast, high-hostility non-smokers subjects demonstrated dramatic metabolic changes to low dose (3.5 mg patch) as did high-hostility smokers to high dose nicotine (21 mg patch) throughout the brain bilaterally (p<0.025). Correlational analyses demonstrated greater metabolic changes in response to nicotine in subjects with greatest hostility trait measures. The observed differences were not a consequence of plasma nicotine or cotinine levels. These metabolic changes were not observed when subjects performed a sustained attentional task (continuous performance task; CPT). Behaviorally, high-hostility subjects had higher ratings of anger, impatience, irritability and nervousness, and lower ratings of happiness, relaxation and curiosity than low-hostility subjects. Smokers had significantly greater scores on impatience and restlessness than non-smokers. This PET study demonstrates a conspicuous lack of the brain metabolic response to nicotine in low-hostility non-smokers in contrast to a dramatic brain response to nicotine in high hostility subjects. This biological difference in brain metabolic response to nicotine between high and low hostility trait subjects may explain differences in susceptibility to nicotine dependence.

Adolescent↗

PubMed2003

Predicting suicidal risk in schizophrenic and schizoaffective patients in a prospective two-year trial.

BACKGROUND: Enhanced ability to reliably identify risk factors for suicidal behavior permits more focused decisions concerning treatment interventions and support services, with potential reduction in lives lost to suicide. METHODS: This study followed 980 patients at high risk for suicide in a multicenter prospective study for 2 years after randomization to clozapine or olanzapine. A priori predictors related to diagnosis, treatment resistance, and clinical constructs of disease symptoms were evaluated as possible predictors of subsequent suicide-related events. RESULTS: Ten baseline univariate predictors were identified. Historical predictors were diagnosis of schizoaffective disorder, history or current use at baseline of alcohol or substance abuse, cigarette smoking, number of lifetime suicide attempts, and the number of hospitalizations in the previous 36 months to prevent suicide. Predictive clinical features included greater baseline scores on the InterSePT scale for suicidal thinking, the Covi Anxiety Scale, the Calgary Depression Scale (CDS), and severity of Parkinsonism. Subsequent multivariate analysis revealed the number of hospitalizations in the previous 36 months, baseline CDS, severity of Parkinson's, history of substance abuse, and lifetime suicide attempts. Clozapine, in general, was more effective than olanzapine in decreasing the risk of suicidality, regardless of risk factors present. CONCLUSIONS: This is the first prospective analysis of predictors of suicide risk in a large schizophrenic and schizoaffective population judged to be at high risk for suicide. Assessment of these risk factors may aid clinicians in evaluating risk for suicidal behaviors so that appropriate interventions can be made.

Adult↗

PubMed2003

MRNA expression patterns and distribution of white matter neurons in dorsolateral prefrontal cortex of depressed patients differ from those in schizophrenia patients.

BACKGROUND: Schizophrenia, bipolar illness, and major depressive disorder have distinct presentations, but share some common symptoms. Hence, some common cellular and molecular abnormalities may be identifiable in these disorders. METHODS: We examined cell-specific markers in the dorsolateral prefrontal cortex of brains from 18 patients with bipolar or major depressive disorder, and 18 matched controls, using in situ hybridization histochemistry and staining for nicotinamide-dinucleotide phosphate-diaphorase (NADPH). The distribution of NADPH-positive interstitial cells of the white matter and the expression of the mRNA for the 67 KD form of glutamic acid decarboxylase (GAD(67)) had previously been shown to be altered in prefrontal cortex of schizophrenics. Other markers identifying glutamatergic neuronal populations were alpha-type II calcium/calmodulin dependent protein kinase (CAMKII-alpha), brain derived neurotrophic factor, (BDNF) and the putative transcription factor, T-brain-1 (TBR1). RESULTS: Expression of GAD67 and the distribution of NADPH-positive cells in the white matter were not significantly altered in the dorsolateral prefrontal cortex of depressed subjects. Expression of CAMKII-alpha and TBR1 mRNAs was significantly increased in bipolar patients but not in major depressed patients, and there was a trend toward reduced BDNF expression in both groups. Abnormal patterns of gene expression and neuronal distribution in schizophrenics are markedly different from those in depressed patients. CONCLUSIONS: The findings that TBR1 and CAMKII-alpha expression is increased only in bipolar patients suggests abnormalities of specific genes related to a major cortical cell type and its connectivity.

Adult↗

PubMed2003

Neurocognitive performance does not correlate with suicidality in schizophrenic and schizoaffective patients at risk for suicide.

BACKGROUND: Almost 50% of schizophrenic persons attempt suicide at some time in their lives and 9-13% of patients ultimately commit suicide. While numerous studies have elucidated the relationship between psychiatric symptomatology and neurocognition in patients with schizophrenia, this is the first report, to our knowledge, to investigate the relationship between suicidal behavior and neurocognition in schizophrenia and schizoaffective disorder. METHODS: A subgroup of 188 patients participating in the InterSePT trial was assessed at baseline with an extensive neurocognitive battery and measures of suicidality and psychiatric symptomatology. RESULTS: Measures of suicidality did not significantly correlate with neurocognitive performance. Confirmatory analyses between patients currently judged to be at high and low risk for suicide also revealed no neurocognitive differences. Consistent with previous studies, poor neurocognitive performance tended to be modestly correlated with the Positive and Negative Syndrome Rating Scale (PANSS) negative symptom scale. The relationship between suicidality and neurocognitive performance was similar for schizoaffective and schizophrenic patients. CONCLUSIONS: The findings suggest that suicidality in patients with schizophrenia and schizoaffective disorder is not correlated with cognition and may, in fact, be a separate domain worthy of investigation and intervention.

Adult↗

PubMed2003

Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder.

BACKGROUND: Aripiprazole is a dopamine D2 receptor partial agonist with partial agonist activity at serotonin 5HT1A receptors and antagonist activity at 5HT2A receptors. This multicenter trial examined the efficacy, safety, and tolerability of aripiprazole in patients with acute exacerbation of schizophrenia or schizoaffective disorder. METHODS: In this 4-week double-blind study, 404 patients were randomized to 20 mg/d (n = 101) or 30 mg/d (n = 101) of aripiprazole, placebo (n = 103), or 6 mg/d of risperidone (n = 99). Efficacy assessments included Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression scores. Safety and tolerability evaluations included extrapyramidal symptoms and effects on weight, prolactin, and corrected QT (QTc) interval. RESULTS: Aripiprazole (20 and 30 mg/d) and risperidone (6 mg/d) were significantly better than placebo on all efficacy measures. Separation from placebo occurred at week 1 for PANSS total and positive scores with aripiprazole and risperidone and for PANSS negative scores with aripiprazole. There were no significant differences between aripiprazole and placebo in mean change from baseline in the extrapyramidal symptom rating scales. Mean prolactin levels decreased with aripiprazole but significantly increased 5-fold with risperidone. Mean change in QTc interval did not differ significantly from placebo with any active treatment group. Aripiprazole and risperidone groups showed a similar low incidence of clinically significant weight gain. CONCLUSIONS: Aripiprazole is effective, safe, and well tolerated for the positive and negative symptoms in schizophrenia and schizoaffective disorder. It is the first non-D2 receptor antagonist with clear antipsychotic effects and represents a novel treatment development for psychotic disorders.

Adult↗

PubMed2003

Alzheimer disease and other dementias.

Dementias become more prevalent with increasing age. As the growth in the geriatric population increases, so does their incidence. Risk factor profiling, neuroimaging, and neurocognitive testing are helping provide objective evidence for determining between normal aging and cognitive deficit states. The diagnosis usually can be made, however, by a careful interview of the patient and a reliable informant and a detailed physical examination with emphasis on the neurologic and mental status examinations, followed by standard laboratory testing. Earlier therapeutic intervention can make a long-term difference in outcome. Distinguishing variants of dementias grants the clinician an opportunity of intervening based on etiology and similarities in neurotransmitter deficit states. Palliative ways of slowing progressive decline are available primarily by way of ChEIs, although no cures yet exist for the dementias. Optimizing current treatments makes sense in improving the quality of life of sufferers.

Aged↗

PubMed2003

Strategies for continued successful treatment of Alzheimer's disease: switching cholinesterase inhibitors.

Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD. Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine. In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.

Alzheimer Disease↗

PubMed2003

Effectiveness of switching to ziprasidone for stable but symptomatic outpatients with schizophrenia.

BACKGROUND: Many outpatients with schizophrenia experience persistent symptoms or side effects on their current antipsychotic regimen. Few studies have prospectively examined the effects of the prior medication or switching method on the safety and efficacy of a newly available antipsychotic. Efficacy and tolerability of ziprasidone were evaluated in patients with DSM-IV schizophrenia or schizoaffective disorder who were switched from conventional or atypical antipsychotics in three 6-week, multicenter, randomized, open-label, parallel-group trials. METHOD: Stable outpatients with persistent symptoms or troublesome side effects on (1) conventional antipsychotic (N = 108), (2) olanzapine (N = 104), or (3) risperidone (N = 58) therapy were switched to an open-label, 6-week, flexible-dose trial of ziprasidone (40-160 mg/day). Patients were randomly assigned at baseline to 1 of 3 switching schedules during the first week of ziprasidone therapy. Baseline and outcome assessments included Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions of Severity (CGI-S) ratings. RESULTS: All 3 switching strategies were well tolerated for all 3 patient groups. After 6 weeks on ziprasidone therapy, significant (p <.05) improvements were observed on all major symptom measures and almost all subscales for all switched subgroups. CONCLUSION: Switching stable but symptomatic outpatients from their previous antipsychotic to ziprasidone was generally well tolerated and was associated with symptom improvements 6 weeks later. Improvements occurred in patients recently on other first-line atypical antipsychotic, as well as in those on conventional antipsychotic, treatment. While limitations of switching study designs do not permit interpretation of comparative efficacy, these studies suggest that outpatients who partially respond to conventional antipsychotics, risperidone, or olanzapine may experience improved control of psychotic symptoms following a switch to ziprasidone.

Adolescent↗

PubMed2002

Pharmacogenomics in schizophrenia: the quest for individualized therapy.

There is strong evidence to suggest that genetic variation plays an important role in inter-individual differences in medication response and toxicity. The rapidly evolving disciplines of pharmacogenetics and pharmacogenomics seek to uncover this genetic variation in order to predict treatment outcomes. The goal is to be able to select the drugs with the greatest likelihood of benefit and the least likelihood of harm in individual patients, based on their genetic make-up-individualized therapy. Pharmacogenomic studies utilize genomic technologies to identify chromosomal areas of interest and novel putative drug targets, while pharmacogenetic strategies rely on studying sequence variations in candidate genes suspected of affecting drug response or toxicity. The candidate gene variants that affect function of the gene or its protein product have the highest priority for investigation. This review will provide demonstrative examples of functional candidate gene variants studied in a variety of antipsychotic response phenotypes in the treatment of schizophrenia. Serotonin and dopamine receptor gene variants in clozapine response will be examined, and in the process the need for sub-phenotypes will be pointed out. Our recent pharmacogenetic studies of the subphenotype of neurocognitive functioning following clozapine treatment and the dopamine D(1) receptor gene (DRD1) will be presented, highlighting our novel neuroimaging data via [(18)F]fluoro-2-deoxy-D-glucose (FDG) metabolism position emission tomography (PET) that demonstrates hypofunctioning of several brain regions in patients with specific dopamine D(1) genotype. Preliminary candidate gene studies investigating the side-effect of clozapine-induced weight gain are also presented. The antipsychotic adverse reaction of tardive dyskinesia and its association with the dopamine D(3) receptor will be critically examined, as well as the added influence of antipsychotic metabolism via the cytochrome P450 1A2 gene (CYP1A2 ). Results that delineate the putative gene-gene interaction between DRD3 and CYP1A2 are also presented. We have also utilized FDG-PET subphenotyping to demonstrate increased brain region activity in patients who have the dopamine D(3) genotype that confers increased risk for antipsychotic induced tardive dyskinesia. The merits and weaknesses of neuroimaging technologies as applied to pharmacogenetic analyses are discussed. To the extent that the above data become more widely verified and replicated, the field of psychiatry will move closer to clinically meaningful tests that will be useful in deciding the best drug for each individual patient.

Antipsychotic Agents↗

PubMed2002

Brain metabolic effects of Neotrofin in patients with Alzheimer's disease.

Neotrofin, a reported inducer of CNS neurotrophic factor synthesis and release, with memory-enhancing activity and demonstrated restoration of age-induced memory deficits in animals, was tested in patients with mild to moderate Alzheimer's disease. Nineteen subjects were treated with 1 week of low-dose (150 mg per day) and 1 week of high-dose (500 or 1000 mg per day) Neotrofin. Cognitive composite scores demonstrated improvement in memory (F=9.6, P=0.0004), executive functioning (P=0.004), and attention (P=0.004). PET scanning was obtained before, after low, and after high dosing. The brain areas most affected were the cerebellum, and sensory and prefrontal cortices, where increases in GMR (Glucose Metabolic Rate) were observed. Increases and decreases were observed in the posterior superior temporal (BA 22), parahippocampal, inferior temporal (BA 37, 20), and fusiform gyri as well as the superior parietal lobule and postcentral gyrus. There were strong hemispheric differences, producing opposite metabolic effects in homologous brain regions. Subcortically, the posterior thalamic region, meso-pontine tegmentum, and tectum had increases in GMR on the left side. At the low dose, GMR was generally increased, but to a lesser degree. The brain areas subserving memory, attention and executive functions were significantly altered in GMR by Neotrofin; however, the directions of these changes were complex. There were significant correlations between improvement in memory and executive function in brain areas involved in circuits subserving these functions. Thus, Neotrofin appears to induce metabolic changes in brain regions involved in circuits underlying memory, attention, and executive functioning.

Aged↗

PubMed2002

Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia.

BACKGROUND: The neurotransmitters dopamine and glutamate have been implicated in the prefrontal dysfunction associated with schizophrenic illness. Studies suggest that the D1 subclass of dopamine receptor and the N-methyl-D-aspartate subclass of glutamate receptor are involved in this prefrontal dysfunction. These 2 receptors regulate, in opposing directions, the amount of phosphorylated activated DARPP-32, a potent inhibitor of protein phosphatase 1 that modulates the activity of several classes of receptors and ion channels. Thus, DARPP-32 occupies a key regulatory position, and may play an important role in the pathophysiological changes in dopamine and glutamate function reported in patients with schizophrenia. METHODS: The amounts of DARPP-32, synapsin I, and the alpha subunit of calcium/calmodulin-dependent protein kinase II were measured by immunoblotting in postmortem samples from 14 schizophrenic subjects and their age-, gender-, and autolysis time-matched control subjects. Possible confounding influences of neuroleptic treatment were analyzed by comparing subjects with Alzheimer disease who were and were not treated with neuroleptic agents. RESULTS: DARPP-32 was significantly reduced in the dorsolateral prefrontal cortex in more schizophrenic subjects relative to matched controls. The ratios of 2 other synaptic phosphoproteins, synapsin I and the alpha subunit of calcium/calmodulin-dependent protein kinase II, did not differ between schizophrenic and control subjects, nor between subjects with Alzheimer disease who were and were not treated with neuroleptic agents. CONCLUSIONS: Our findings are consistent with a selective reduction in DARPP-32 levels in schizophrenic subjects. This may be involved in the prefrontal dysfunction associated with schizophrenia.

Adult↗

PubMed2002

Open-label study of the effect of combination quetiapine/lithium therapy on lithium pharmacokinetics and tolerability.

OBJECTIVE: The aim of this study was to assess the effect of oral quetiapine on the steady-state pharmacokinetics of lithium. METHODS: This was an open-label trial in patients with schizophrenia, schizoaffective disorder, or bipolar disorder who had demonstrated tolerability to combination lithium/ antipsychotic therapy. Patients received lithium for at least 1 week before screening and throughout the 18-day trial. Quetiapine was coadministered in fixed, stepwise, increasing doses of 25 to 250 mg TID on days 4 through 11, and maintained at 250 mg TID on days 12 through 14. Blood samples were drawn to monitor plasma concentrations of lithium and quetiapine. Psychiatric assessments included the Brief Psychiatric Rating Scale, the Clinical Global Impression severity of illness item, and the modified Scale for the Assessment of Negative Symptoms. Neurologic function was assessed using the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale. Other assessments included clinical laboratory testing, electrocardiography, physical examinations, and monitoring for spontaneously reported adverse events. RESULTS: Nine men and 1 woman (mean [SE] age, 32.8 [1.9] years; mean [SE] body weight, 87.6 [3.3] kg) entered and completed the 18-day trial. Eight patients had bipolar disorder, 1 had paranoid schizophrenia, and 1 had schizoaffective disorder. Morning trough concentrations of lithium in serum (days 2, 6, 8, 10, 12, 14, and 17), as well as quetiapine and 2 of its metabolites in plasma (days 12, 13, and 14), did not appear to vary noticeably. Small increases were observed in the mean values of the area under the 12-hour serum lithium concentration-time curve and the maximum and minimum observed serum lithium concentrations when quetiapine was added to the lithium regimen. However, the increases were not considered clinically relevant by the investigators and were not statistically significant. A total of 91 adverse events were reported, 67 (73.6%) of which were not attributed to trial treatment. The most commonly reported adverse events during coadministration of lithium and quetiapine were somnolence (90.0% [9/10]), asthenia (70.0% [7/10]), dry mouth (30.0% [3/10]), nausea (30.0% [3/10]), vomiting (30.0% [3/10]), dizziness (30.0% [3/10]), tremor (30.0% [3/10]), and insomnia (20.0% [2/10]). There were no serious adverse events. CONCLUSIONS: Measures of lithium and quetiapine concentrations did not vary significantly during combination therapy. Coadministered lithium and quetiapine were well tolerated in the patients studied.

Adult↗

PubMed2002

The ABC of Alzheimer's disease: ADL and improving day-to-day functioning of patients.

Alzheimer's disease (AD) is characterized by deterioration in the ability to perform activities of daily living (ADL) in addition to loss of cognitive function and behavioral changes. This decline in day-to-day functioning is increasingly recognized as a source of considerable social, health, and economic costs. Inability to perform ADL results in growing caregiver burden and may lead to the eventual need for alternative care or nursing home placement. The measurement of ADL, which enables monitoring of the effectiveness of therapeutic interventions, can be performed using a number of inventories including the Progressive Deterioration Scale (PDS), the Disability Assessment for Dementia (DAD), and the Alzheimer Disease Cooperative Study ADL (ADCS/ADL) assessment scale. Clinical studies using these and other scales have indicated that cholinesterase (ChE) inhibitors offer an effective approach to treating the functional decline of AD. Donepezil, rivastigmine, and galantamine have been shown in some studies to prevent or slow decline in ADL over treatment periods of one to two years. For instance, in a 24-week study in subjects with moderate to severe AD, donepezil-treated patients remained stable compared with the placebo-treated patients. Rivastigmine has shown improvement or stabilization of PDS scores in patients with mild to moderate disease following 26 weeks of treatment and slowed deterioration in patients with more severe disease. Evidence to date suggests that these agents may not be equally effective at slowing or stabilizing loss in ADL over time and that these differences may reflect differences in pharmacology. In addition to inhibition of acetylcholinesterase (AChE), these compounds have other putative differences in mechanisms of action. Galantamine allosterically modulates the nicotinic receptor and may prevent the loss of ADL. Rivastigmine robustly inhibits butyrylcholinesterase in addition to AChE and therefore acts as a dual ChE inhibitor. Comparative studies evaluating the differential effects of these ChE inhibitors on ADL are awaited.

Activities of Daily Living↗

PubMed2002

The safety and pharmacokinetics of quetiapine when coadministered with haloperidol, risperidone, or thioridazine.

The effects of haloperidol, risperidone, and thioridazine on the pharmacokinetics and side-effect profile of quetiapine were investigated in 36 patients with schizophrenia, schizoaffective disorder, or bipolar disorder in a single-center, two-period, multiple-dose, open-label, randomized trial. Over a one-to two-week period, quetiapine doses were escalated to 300 mg twice daily (bid). Patients were then treated for at least 7 days at the target quetiapine dose and subsequently entered into the combination therapy period, receiving haloperidol (7.5 mg, bid), risperidone (3 mg, bid), or thioridazine (200 mg, bid) for 8.5 days (after 3 days of dose escalation). Key assessments included the pharmacokinetics of quetiapine at steady state (area under the curve within a dosing interval [AUCtSS], maximum [CmaxSS], and minimum [CminSS] observed plasma concentrations, and oral clearance [Cl/f]), as well as the UKU Side Effect Rating Scale scores and safety evaluations. Neither risperidone nor haloperidol had significant effects on quetiapine pharmacokinetics. However, thioridazine produced statistically significant changes, decreasing the least squares means values of the AUCtSS, CmaxSS, and CminSS by 40%, 47%, and 31%, respectively, and increasing Cl/f by 68%. Increases in the following adverse events were noted during coadministration: somnolence (risperidone), insomnia and dry mouth (all three coadministered therapies), and dizziness (thioridazine). UKU side effect items that became worse in >or= 25% of patients during each coadministration period included sedation and increased sleep duration. Results of laboratory tests, electrocardiograms, and vital sign measurements revealed few clinically important changes. Clinical stability can be maintained with good tolerability during the transition from quetiapine monotherapy to periods of coadministration with haloperidol, risperidone, or thioridazine. Coadministration of either haloperidol or risperidone did not have any important effects on the steady-state pharmacokinetics of quetiapine. Thioridazine significantly increased the oral clearance of quetiapine. Increased doses of quetiapine may be necessary to control psychotic symptoms when thioridazine is coadministered with quetiapine.

Adolescent↗

PubMed2002

Effect of fluoxetine and imipramine on the pharmacokinetics and tolerability of the antipsychotic quetiapine.

The effects of fluoxetine and imipramine on the pharmacokinetics and nonpsychiatric side effect profile of quetiapine fumarate were investigated in 26 patients with schizophrenia, schizoaffective disorder, or bipolar disorder in a multicenter, two-period, multiple-dose, open-label, randomized trial. Over a 1- to 2-week period, patients were titrated to a 300-mg twice-daily dose of quetiapine. Patients treated for at least 7 days at the target dose entered a combination therapy period, receiving fluoxetine (60 mg daily) or imipramine (75 mg twice daily) for 8 days. Key assessments included pharmacokinetic analysis of quetiapine, the Udvalg for kliniske undersøgelser (UKU) Side Effect Rating Scale, and safety evaluations (e.g., adverse events, electrocardiograms, laboratory tests, and vital signs). Fluoxetine increased the quetiapine area under the plasma concentration time curve during a 12-hour interval (+12%), maximum plasma concentration during the dosing interval (C(ss)(max); +26%), and minimum plasma concentration at the end of the dosing interval (+8%), although it decreased oral clearance (-11%). The change in C(ss)(max) was statistically although not clinically significant. Imipramine did not affect the pharmacokinetics of quetiapine. Overall, scores on the UKU Side Effect Rating Scale improved during combination therapy with either agent, and no statistically significant deterioration was observed for any item. For safety assessments, the only clinically remarkable event was an imipramine-associated complete left bundle branch block in one patient. No unexpected side effects were reported. In conclusion, combination therapy with quetiapine and fluoxetine or imipramine had a minimal effect on quetiapine pharmacokinetics and was well tolerated.

Adolescent↗

PubMed2002

A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron emission tomography.

OBJECTIVE: Positron emission tomography (PET) was used to compare cerebral metabolic patterns in schizophrenic subjects with predominantly negative symptoms (alogia, affective flattening, avolition, and attentional impairment) and in those with predominantly positive symptoms. METHOD: Fourteen right-handed male subjects with DSM-IV schizophrenia were assigned to groups with predominantly negative or predominantly positive symptoms on the basis of their post-drug-washout scores on the Positive and Negative Syndrome Scale. The patients were compared to seven age- and gender-matched normal volunteers. PET scans with [(18)F]fluorodeoxyglucose were obtained during a degraded Continuous Performance Task to measure absolute glucose metabolic rates. Statistical parametric mapping was used to estimate the regional metabolic differences between groups. RESULTS: The subjects with predominantly negative symptoms had significant differences in glucose metabolic rates, compared to both the subjects with predominantly positive symptoms and the normal subjects. Negative symptom subjects had a lower glucose metabolic rate in the right hemisphere, especially in the temporal and ventral prefrontal cortices, compared to the other groups, and higher metabolic rates in the cerebellar cortex and in the lower deep cerebellar nuclei. Negative symptom subscale scores were negatively correlated with glucose metabolic rates for most of the brain areas that differentiated subjects with predominantly negative symptoms from those with predominantly positive symptoms. CONCLUSIONS: Schizophrenic subjects with predominantly negative symptoms have greater metabolic abnormalities than subjects with predominantly positive symptoms, particularly in frontal, temporal, and cerebellar circuitry. These results are consistent with abnormalities in corticocortical, corticobasal ganglia, mesocortical dopamine, and cerebellar-thalamic-prefrontal circuits, which may underlie the negative symptoms of schizophrenia.

Adult↗