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ABSTRACT: Bipolar Disorder (BD) is a chronic illness characterized by significant neurocognitive impairment and functional deficits. Functional status is typically assessed with self-report or observer ratings restricted by poor participant insight and subjective judgment, while application of performance-based measures has been limited. We assessed functional ability in manic, depressed, and euthymic BD individuals using the UCSD Performance-Based Skills Assessment (UPSA-2), which simulates real-world tasks such as medication management. UPSA-2 was administered to 17 manic or hypomanic BD, 14 depressed BD, 23 euthymic BD, and 28 healthy comparison (HC) participants matched for age, education, and IQ. Psychopathology was quantified with the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), and the Positive and Negative Syndrome Scale (PANSS); executive functioning was assessed with the Wisconsin Card Sorting Task (WCST). All BD groups exhibited functional ability deficits on the UPSA-2 and impaired performance on the WCST compared to HC. UPSA-2 scores were lower in manic/hypomanic subjects relative to other BD participants and mania symptoms correlated with functional impairment. Poor WCST performance was also associated with worse UPSA-2 function. In summary, BD functional deficits occur across different phases of the disorder and may be impacted by symptom severity and associated with executive dysfunction.
Psychiatry research. 05/2013;
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ABSTRACT: Bipolar disorder (BD) is a pervasive neuropsychiatric disorder characterized by episodes of mania and depression. The switch between mania and depression may reflect seasonal changes and certainly can be affected by alterations in sleep and circadian control. The circadian locomotor output cycles kaput (CLOCK) protein is a key component of the cellular circadian clock. Mutation of the Clock gene encoding this protein in ClockΔ19 mutant mice leads to behavioral abnormalities reminiscent of BD mania. To date, however, these mice have not been assessed in behavioral paradigms that have cross-species translational validity. In the present studies of ClockΔ19 and wildtype (WT) littermate mice, we quantified exploratory behavior and sensorimotor gating, which are abnormal in BD manic patients. We also examined the saccharin preference of these mice and their circadian control in different photoperiods. ClockΔ19 mice exhibited behavioral alterations that are consistent with BD manic patients tested in comparable tasks, including hyperactivity, increased specific exploration, and reduced sensorimotor gating. Moreover, compared to WT mice, ClockΔ19 mice exhibited a greater preference for sweetened solutions and greater sensitivity to altered photoperiod. In contrast with BD manic patients however, ClockΔ19 mice exhibited more circumscribed movements during exploration. Future studies will extend the characterization of these mice in measures with cross-species translational relevance to human testing.
Behavioural brain research 04/2013; · 3.22 Impact Factor
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ABSTRACT: Sensorimotor inhibition, or the ability to filter out excessive or irrelevant information, theoretically supports a variety of higher-level cognitive functions. Impaired inhibition may be associated with increased impulsive and risky behavior in everyday life. Individuals infected with HIV frequently show impairment on tests of neurocognitive function, but sensorimotor inhibition in this population has not been studied and may be a contributor to the profile of HIV-associated neurocognitive disorders (HAND). Thirty-seven HIV-infected individuals (15 with HAND) and 48 non-infected comparison subjects were assessed for prepulse inhibition (PPI), an eyeblink startle paradigm measuring sensorimotor gating. Although HIV status alone was not associated with PPI deficits, HIV-positive participants meeting criteria for HAND showed impaired PPI compared to cognitively intact HIV-positive subjects. In HIV-positive subjects, PPI was correlated with working memory but was not associated with antiretroviral therapy or illness factors. In conclusion, sensorimotor disinhibition in HIV accompanies deficits in higher-order cognitive functions, although the causal direction of this relationship requires investigation. Subsequent research on the role of sensorimotor gating on decision-making and risk behaviors in HIV may be indicated. (JINS, 2013, 19, 1-9).
Journal of the International Neuropsychological Society 04/2013; · 2.76 Impact Factor
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ABSTRACT: BACKGROUND: Suicidal ideation and attempted suicide are important presenting complaints in the Emergency Department (ED). The Joint Commission established a National Patient Safety Goal that requires screening for suicidal ideation to identify patients at risk for suicide. OBJECTIVES: Given the emphasis on screening for suicidal ideation in the general hospital and ED, it is important for Emergency Physicians to be able to understand and perform suicide risk assessment. METHODS: A review of literature was conducted using PubMed to determine important elements of suicide assessment in adults, ages 18 years and over, in the ED. Four typical ED cases are presented and the assessment of suicide risk in each case is discussed. RESULTS: The goal of an ED evaluation is to appropriately determine which patients are at lowest suicide risk, and which patients are at higher or indeterminate risk such that psychiatry consultation is warranted while the patient is in the ED. Emergency clinicians should estimate this risk by taking into account baseline risk factors, such as previous suicide attempts, as well as acute risk factors, such as the presence of a suicide plan. CONCLUSION: Although a brief screening of suicide risk in the ED does not have the sensitivity to accurately determine which patients are at highest risk of suicide after leaving the ED, patients at lowest risk may be identified. In these low-risk patients, psychiatric holds and real-time psychiatric consultation while in the ED may not be needed, facilitating more expeditious dispositions from the ED.
Journal of Emergency Medicine 10/2012; · 1.31 Impact Factor
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ABSTRACT: Methamphetamine (METH) dependence is frequently comorbid with HIV infection. Both factors are independently characterized by inhibitory deficits, which may manifest as increased motor activity, inappropriate perseverative behavior, and elevated exploratory responses to novel stimuli, but the effect of combined METH exposure and HIV is not well understood. In this study, we administered a chronic escalation/binge regimen of METH or vehicle treatment to wildtype (WT) or transgenic (tg) mice expressing the HIV-1 gp120 envelope protein and quantified disinhibition during the 7 days following drug withdrawal. We hypothesized that gp120tg mice administered chronic METH would exhibit more pronounced inhibitory deficits compared to vehicle-treated WT or gp120tg animals. Our results showed that METH treatment alone increased novel object interaction while female METH-treated gp120tg mice exhibited the highest level of exploration (holepoking) compared to other female mice. Transgenic mice exhibited fewer rears relative to WT, slightly less locomotion, and also demonstrated a trend toward more perseverative motor patterns. In summary, both METH treatment and gp120 expression may modify inhibition, but such effects are selective and dependent upon variations in age and sex that could impact dopamine and frontostriatal function. These findings illustrate the need to improve our knowledge about the combined effects of HIV and substance use and facilitate improved treatment methods for comorbid disease and drug dependence.
Behavioural brain research 08/2012; 236C:210-220. · 3.22 Impact Factor
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ABSTRACT: Cognitive deficits are a prominent, disabling component of schizophrenia and current pharmacological treatments have demonstrated limited efficacy in their amelioration. Oxytocin - though it has shown promise as a novel antipsychotic in multiple clinical trials - has as-yet poorly characterized effects on cognition, with some evidence indicating an amnestic profile.
As part of a previously reported trial of chronic adjunctive oxytocin in schizophrenia, we measured its effect on two cognitive tests: the CVLT (California Verbal Learning Test) and the LNS (Letter Number Sequence). Tests were performed at baseline and after 3 weeks of treatment.
We found no evidence for an amnestic effect and, in fact, significantly better performance with oxytocin on several subtests of the CVLT; namely total Recall trials 1-5 (p=0.027), short delayed free recall (p=0.032) and total recall discrimination (p=0.020). In contrast we found no difference between placebo and oxytocin on LNS performance.
This is the first report we are aware of documenting a beneficial effect of oxytocin on cognition in schizophrenia. Though from a small sample (n=15), these data both offset past concerns about oxytocin's amnestic effects, and may auger another potential benefit in addition to the already-demonstrated salutary effects on other components of the illness.
Biological Psychiatry 06/2012; 139(1-3):207-10. · 8.28 Impact Factor
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ABSTRACT: Agitation has significant consequences for patients and staff. When verbal techniques fail, expert guidelines recommend the use of second-generation antipsychotics (SGAs). Perhaps out of familiarity with haloperidol and benzodiazepines, emergency department (ED) clinicians often pair SGAs with benzodiazepines as well. Use of SGAs such as olanzapine in alcohol-intoxicated (ETOH+) patients or with benzodiazepines is not well studied and may be associated with vital sign abnormalities.
This is a structured chart review of all patient visits who received either oral or intramuscular (i.m.) olanzapine in an academic ED from 2004 to 2010 and who had systolic blood pressure, heart rate, and oxygen saturation documented before medication administration and within 4 hours afterwards.
Four hundred eighty-two patient visits received olanzapine; 275 patient visits (225 oral, 50 i.m.) had vital signs documented. Neither route of administration, concurrent benzodiazepines, nor ingestion of ETOH were associated with significant decreases in systolic BP or heart rate (P = ns for all comparisons). Decreases in oxygen saturations, however, were significantly larger in ETOH+ patients who received i.m. olanzapine or i.m. olanzapine + benzodiazepines. Route of administration, concurrent benzodiazepines, nor ingestion of ETOH was associated with significant decreases in systolic blood pressure or heart rate (p = ns for all comparisons). Decreases in oxygen saturations, however, were significantly larger in ETOH+ patients who received i.m. olanzapine or i.m. olanzapine + benzodiazepines.
Oral olanzapine was not associated with significant vital sign changes in ED patients. Intramuscular olanzapine also was not associated with vital sign changes in ETOH- patients. In ETOH+ patients, i.m. olanzapine was associated with significant oxygen desaturations. In ETOH+ ED patients, oral olanzapine (with or without benzodiazepines) or haloperidol may be safer choices. ETOH+ patients may have differential effects with the use of i.m. SGAs such as olanzapine and should be studied separately in drug trials.
The American journal of emergency medicine 05/2012; 30(7):1196-201. · 1.54 Impact Factor
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ABSTRACT: Published research on agitation is limited by the difficulty in generalizing findings from trials using moderately agitated, carefully selected patients treated with single agents. More specifically, there are few comparative studies examining common intramuscular (IM) regimens (ie, haloperidol with or without benzodiazepines) with IM atypical antipsychotics. Therefore, we conducted a retrospective chart review to compare IM olanzapine and haloperidol in a "real-world" population with agitation.
We performed a retrospective evaluation of charts from 146 consecutive emergency department patients who received either IM haloperidol or IM olanzapine for agitation. We used a clinically oriented proxy marker of efficacy--the necessity for additional medication intervention for agitation (AMI)--as our primary outcome measure.
Additional medication intervention for agitation was required by 43% (13/30) patients when haloperidol was given alone and by 18% (13/72) when haloperidol was given with a benzodiazepine. In the case of olanzapine, AMI was required by 29% (6/21) of patients receiving olanzapine alone and by 18% (2/11) of patients given olanzapine plus a benzodiazepine. A significant percentage of patients had clinical characteristics (nonpsychiatric triage complaint, drug/alcohol use, severe agitation) that differ from more selective samples.
Overall, these finding suggest that in a naturalistic emergency department setting, haloperidol monotherapy is less effective--at least in requiring AMI--than olanzapine with or without a benzodiazepine or haloperidol plus a benzodiazepine. Moreover, these later 3 regimens seemed comparable. Prospective studies examining the treatment of real-world agitation, including head-to-head comparisons of the haloperidol-benzodiazepine combination with newer IM antipsychotics, are needed.
Journal of clinical psychopharmacology 04/2012; 32(3):317-22. · 5.09 Impact Factor
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ABSTRACT: This case describes the clinical course of a cannabis-dependent individual entering a 12-week abstinence-based research program. The case illustrates the effects of chronic, heavy cannabis use on executive functions at three time points: 1) 24 hours of abstinence; 2) 4 weeks of abstinence; and 3) 12 weeks of abstinence. It is followed by discussions by two clinical psychologists and a psychiatrist. The findings described here have important clinical implications, as executive functions have a vital role in treatment participation and in sustaining recovery. It should be of particular interest to clinicians who work with people with cannabis use disorders.
Journal of Addiction Medicine 03/2011; 5(1):9-15. · 1.95 Impact Factor
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ABSTRACT: Exploration and novelty seeking are cross-species adaptive behaviors that are dysregulated in bipolar disorder (BD) and are critical features of the illness. While these behaviors have been extensively quantified in animals, multivariate human paradigms of exploration are lacking. The human Behavioral Pattern Monitor (hBPM), a human version of the animal open field, identified a signature pattern of hyper-exploration in manic BD patients, but whether exploratory behavior changes with treatment is unknown. The objective of this study was to assess the sensitivity of the hBPM to changes in manic symptoms, a necessary step towards elucidating the neurobiology underlying BD.
Twelve acutely hospitalized manic BD subjects and 21 healthy volunteers were tested in the hBPM over three sessions; all subjects were retested one week after their first session and two weeks after their second session. Motor activity, spatial and entropic (degree of unpredictability) patterns of exploration, and interactions with novel objects were quantified. Manic BD patients demonstrated greater motor activity, extensive and more unpredictable patterns of exploration, and more object interactions than healthy volunteers during all three sessions. Exploration and novelty-seeking slightly decreased in manic BD subjects over the three sessions as their symptoms responded to treatment, but never to the level of healthy volunteers. Among healthy volunteers, exploration did not significantly decrease over time, and hBPM measures were highly correlated between sessions.
Manic BD patients showed a modest reduction in symptoms yet still demonstrated hyper-exploration and novelty seeking in the hBPM, suggesting that these illness features may be enduring characteristics of BD. Furthermore, behavior in the hBPM is not subject to marked habituation effects. The hBPM can be reliably used in a repeated-measures design to characterize exploration and novelty seeking and, in parallel with animal studies, can contribute to developing treatments that target neuropsychiatric disease.
PLoS ONE 01/2011; 6(8):e24185. · 4.09 Impact Factor
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ABSTRACT: Methamphetamine (MA) is an addictive psychostimulant associated with neurocognitive impairment, including inhibitory deficits characterized by a reduced ability to control responses to stimuli. While various domains of inhibition such as exaggerated novelty seeking and perseveration have been assessed in rodents by quantifying activity in open-field tests, similar models have not been utilized in human substance abusers. We recently developed a cross-species translational human open-field paradigm, the human behavior pattern monitor (hBPM), consisting of an unfamiliar room containing novel and engaging objects. Previous work demonstrated that manic bipolar subjects exhibit a disinhibited pattern of behavior in the hBPM characterized by increased object interactions.
In the current study, we examined the effect of MA dependence on inhibitory deficits using this paradigm. hBPM activity and object interactions were quantified in 16 abstinent MA-dependent individuals and 18 matched drug-free comparison subjects. The Wisconsin card sorting task (WCST) and the positive and negative syndrome scale (PANSS) were administered to assess executive function and psychopathology.
MA-dependent participants exhibited a significant increase in total object interactions, time spent with objects, and perseverative object interactions relative to comparison subjects. Greater object interaction was associated with impaired performance on the WCST, higher PANSS scores, and more frequent MA use in the past year.
Abstinent MA-dependent individuals exhibited impaired inhibition in the hBPM, displaying increased interaction with novel stimuli. Utilization of this measure may enable assessment of inhibitory deficits relevant to drug-seeking behavior and facilitate development of intervention methods to reduce high-risk conduct in this population.
Psychopharmacologia 01/2011; 215(4):697-707. · 4.08 Impact Factor
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ABSTRACT: Methamphetamine (METH) is an increasing popular and highly addictive stimulant associated with autonomic nervous system (ANS) dysfunction, cardiovascular pathology and neurotoxicity. Heart rate variability (HRV) has been used to assess autonomic function and predict mortality in cardiac disorders and drug intoxication, but has not been characterized in METH use. We recorded HRV in a sample of currently abstinent individuals with a history of METH dependence compared to age- and gender-matched drug-free comparison subjects. HRV was assessed using time domain, frequency domain, and non-linear entropic analyses in 17 previously METH-dependent and 21 drug-free comparison individuals during a 5 minute rest period. The METH-dependent group demonstrated significant reduction in HRV, reduced parasympathetic activity, and diminished heartbeat complexity relative to comparison participants. More recent METH use was associated with increased sympathetic tone. Chronic METH exposure may be associated with decreased HRV, impaired vagal function, and reduction in heart rate complexity as assessed by multiple methods of analysis. We discuss and review evidence that impaired HRV may be related to the cardiotoxic or neurotoxic effects of prolonged METH use.
Addiction Biology 12/2010; 17(3):648-58. · 4.83 Impact Factor
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David Feifel,
Kai Macdonald,
Angel Nguyen,
Patrice Cobb,
Heather Warlan,
Barbara Galangue, Arpi Minassian,
Olga Becker,
Jason Cooper,
William Perry,
Mischelle Lefebvre,
James Gonzales,
Allison Hadley
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ABSTRACT: Both human and animal studies suggest oxytocin may have antipsychotic properties. Therefore, we conducted a clinical trial to directly test this notion.
Nineteen schizophrenia patients with residual symptoms despite being on a stable dose of at least one antipsychotic were enrolled in a randomized, double-blind, crossover study. They received 3 weeks of daily intranasal oxytocin (titrated to 40 IU twice a day) and placebo adjunctive to their antipsychotics. Order of intranasal treatment was randomly assigned and there was a 1-week washout between treatments.
Analysis of the 15 subjects who completed all the study visits revealed that oxytocin significantly reduced scores on the Positive and Negative Symptom Scale (p < .001) and Clinical Global Impression-Improvement Scale (p < .001) compared with placebo at the 3-week end point. No benefit was seen at the early time points. Oxytocin was well tolerated and produced no adverse effects based upon patient reports or laboratory analysis.
The results support the hypothesis that oxytocin has antipsychotic properties and is well tolerated. Higher doses and longer duration of treatment may produce larger benefits and should be evaluated in future studies.
Biological psychiatry 10/2010; 68(7):678-80. · 8.93 Impact Factor
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ABSTRACT: Importance of the field: Asenapine is a new atypical antipsychotic medication with high affinity for D(2) and 5HT(2A) receptors that has been approved by the FDA in adults for the acute treatment of schizophrenia in the USA. The purpose of this review is to describe the compound and examine whether it addresses some of the unmet clinical needs in treating schizophrenia. Areas covered in this review: The development of asenapine is described with attention to its chemistry, pharmacodynamic and pharmacokinetic profile. Preclinical and clinical trials of safety and efficacy are reviewed. The advantages and disadvantages of asenapine relative to other antipsychotic medications are discussed. What the reader will gain: Asenapine will be evaluated for whether it: i) causes a reduction in symptoms of schizophrenia; ii) has a side-effect profile minimizing extrapyramidal symptoms, weight gain and cardiac effects; and iii) affects negative and/or cognitive symptoms. Take home message: Asenapine is a recently approved agent with an acceptable cardiometabolic profile and exhibits similar efficacy as other antipsychotic medications, primarily on positive symptoms of schizophrenia. Relatively less weight gain compared with other agents may confer a notable advantage. Sublingual administration may have positive and negative effects on patient compliance. Potential 'pro-cognitive' effects of asenapine are preliminary and require more investigation.
Expert Opinion on Pharmacotherapy 08/2010; 11(12):2107-15. · 3.20 Impact Factor
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ABSTRACT: Alterations in exploratory behavior are a fundamental feature of bipolar mania, typically characterized as motor hyperactivity and increased goal-directed behavior in response to environmental cues. In contrast, abnormal exploration associated with schizophrenia and depression can manifest as prominent withdrawal, limited motor activity, and inattention to the environment. While motor abnormalities are cited frequently as clinical manifestations of these disorders, relatively few empirical studies have quantified human exploratory behavior. This article reviews the literature characterizing motor and exploratory behavior associated with bipolar disorder and genetic and pharmacological animal models of the illness. Despite sophisticated assessment of exploratory behavior in rodents, objective quantification of human motor activity has been limited primarily to actigraphy studies with poor cross-species translational value. Furthermore, symptoms that reflect the cardinal features of bipolar disorder have proven difficult to establish in putative animal models of this illness. Recently, however, novel tools such as the human behavioral pattern monitor provide multivariate translational measures of motor and exploratory activity, enabling improved understanding of the neurobiology underlying psychiatric disorders.
Neuroscience & Biobehavioral Reviews 07/2010; 34(8):1296-306. · 8.65 Impact Factor
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ABSTRACT: It has been suggested that a cardinal symptom of mania is over-activity and exaggerated goal-directed behavior. Nevertheless, few attempts have been made to quantify this behavior objectively in a laboratory environment. Having a methodology to assess over-activity reliably might be useful in distinguishing manic bipolar disorder (BD) from schizophrenia (SCZ) during highly activated states. In the current study, quantifiable measures of object interaction were assessed using a multivariate approach. Additionally, symptom correlates of over-activity were assessed. Patients admitted to an acute care psychiatric hospital for either BD with mania or SCZ (paranoid and non-paranoid subtypes) as well as non-patient comparison (NC) participants were assessed in an open field setting referred to as the human Behavioral Pattern Monitor (hBPM). Activity and interactions with novel and engaging objects were recorded for 15min via a concealed video camera and rated for exploratory behavior. Both BD and SCZ patients spent more time near the objects and exhibited more overall walking compared to NC. In contrast, BD patients exhibited greater physical contact with objects (number of object interactions and time spent with objects) relative to SCZ patients or NC participants, as well as more perseverative and socially disinhibited behaviors, indicating a unique pattern of over-activity and goal-directed behavior. Further analyses revealed a distinction between SCZ patients according to their subtype. The current study extends our methodology for quantifying exploration and over-activity in a controlled laboratory setting and aids in assessing the overlap and distinguishing characteristics of BD and SCZ.
Psychiatry Research 06/2010; 178(1):84-91. · 2.52 Impact Factor
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ABSTRACT: Bipolar Disorder (BD) is a neuropsychiatric disorder characterized by symptoms ranging from a hyperactive manic state to depression, with periods of relative stability, known as euthymia, in between. Although prognosis for BD sufferers remains poor, treatment development has been restricted due to a paucity of validated animal models. Moreover, most models focus on the manic state of BD with little done to characterize the longitudinal behavior of these models. We recently presented two dopamine transporter (DAT) mouse models of BD mania: genetic (DAT knockdown; KD, mice) and pharmacological (the selective DAT inhibitor GBR 12909). These models exhibit an exploratory profile consistent with the quantified exploratory profile of manic BD patients observed in the cross-species translational test, the Behavioral Pattern Monitor (BPM). To further explore the suitability of these models, we examined the effects of reduced DAT function on the behavior of mice tested after familiarization to the BPM environment. Testing with 16mg/kg GBR 12909 in familiarized mice resulted in a consistent mania-like profile. In contrast, the mania-like profile of DAT KD mice disappears in a familiar environment, with partial reinstatement elicited by the introduction of novelty. In addition, we found that a subthreshold dose of GBR 12909 (9mg/kg) reinstated the mania-like profile in DAT KD mice without affecting wildtype behavior. Thus, the mania-like exploratory profile of DAT KD mice is reduced in a familiar environment, partially reinstated with novelty, but is fully restored when administered a stimulant that is ineffective in wildtype mice. These mice may provide a model of BD from mania to euthymia and back again with stimulant treatment. Acute blockade of the DAT by GBR 12909 however, may provide a consistent model for BD mania.
Pharmacology Biochemistry and Behavior 04/2010; 96(1):7-15. · 2.53 Impact Factor
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ABSTRACT: Methamphetamine (METH) is an increasingly popular and highly addictive psychostimulant with a significant impact on public health. Chronic METH exposure has been associated with neurotoxic effects, profound neuropsychological deficits, and impaired quality of life, but few studies have examined the effect of the drug on the ability to carry out everyday activities. We assessed the effect of METH dependence on everyday functioning using the UCSD Performance-Based Skills Assessment (UPSA-2), a performance-based measure designed to evaluate real-life skills.
UPSA-2 performance was quantified in 15 currently abstinent individuals with a history of METH dependence and 15 drug-free comparison subjects. The Positive and Negative Syndrome Scale (PANSS) and Wisconsin Card Sorting Task (WCST) were administered to assess psychopathology and executive function.
METH-dependent participants exhibited significant impairment on the UPSA-2 total score and several UPSA-2 subscales, including comprehension, finance, transportation, communication, and medication management compared to drug-free comparison subjects. Lower UPSA-2 scores were associated with impaired performance on the WCST, higher PANSS scores, and drug use at an earlier age.
METH dependence may be associated with decreased everyday functioning ability potentially mediated by frontal cortex dysfunction or the emergence of psychopathology related to chronic drug use.
Addictive behaviors 02/2010; 35(6):593-8. · 2.25 Impact Factor
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ABSTRACT: Mania is a core feature of bipolar disorder (BD) that traditionally is assessed using rating scales. Studies using a new human behavioral pattern monitor (BPM) recently demonstrated that manic BD patients exhibit a specific profile of behavior that differs from schizophrenia and is characterized by increased motor activity, increased specific exploration, and perseverative locomotor patterns as assessed by spatial d.
It was hypothesized that disrupting dopaminergic homeostasis by inhibiting dopamine transporter (DAT) function would produce a BD mania-like phenotype in mice as assessed by the mouse BPM.
We compared the spontaneous locomotor and exploratory behavior of C57BL/6J mice treated with the catecholamine transporter inhibitor amphetamine or the selective DAT inhibitor GBR 12909 in the mouse BPM. We also assessed the duration of the effect of GBR 12909 by testing mice in the BPM for 3 h and its potential strain dependency by testing 129/SvJ mice.
Amphetamine produced hyperactivity and increased perseverative patterns of locomotion as reflected in reduced spatial d values but reduced exploratory activity in contrast to the increased exploration observed in BD patients. GBR 12909 increased activity and reduced spatial d in combination with increased exploratory behavior, irrespective of inbred strain. These effects persisted for at least 3 h.
Thus, selectively inhibiting the DAT produced a long-lasting cross-strain behavioral profile in mice that was consistent with that observed in manic BD patients. These findings support the use of selective DAT inhibition in animal models of the impaired dopaminergic homeostasis putatively involved in the pathophysiology of BD mania.
Psychopharmacologia 12/2009; 208(3):443-54. · 4.08 Impact Factor
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William Perry, Arpi Minassian,
Martin P Paulus,
Jared W Young,
Meegin J Kincaid,
Eliza J Ferguson,
Brook L Henry,
Xiaoxi Zhuang,
Virginia L Masten,
Richard F Sharp,
Mark A Geyer
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ABSTRACT: Bipolar mania and schizophrenia are recognized as separate disorders but share many commonalities, which raises the question of whether they are the same disorder on different ends of a continuum. The lack of distinct endophenotypes of bipolar mania and schizophrenia has complicated the development of animal models that are specific to these disorders. Exploration is fundamental to survival and is dysregulated in these 2 disorders. Although exploratory behavior in rodents has been widely studied, surprisingly little work has examined this critical function in humans.
To quantify the exploratory behavior of individuals with bipolar mania and schizophrenia and to identify distinctive phenotypes of these illnesses.
Static group comparison by the use of a novel human open field paradigm, the human Behavioral Pattern Monitor (BPM).
Psychiatric hospital.
Fifteen patients with bipolar mania and 16 patients with schizophrenia were compared with 26 healthy volunteers in the human BPM. The effects of amphetamine sulfate, the selective dopamine transporter inhibitor GBR12909, and the genetic knockdown of the dopamine transporter were compared with controls in the mouse BPM.
The amount of motor activity, spatial patterns of activity, and exploration of novel stimuli were quantified in both the human and mouse BPMs.
Patients with bipolar mania demonstrated a unique exploratory pattern, characterized by high motor activity and increased object exploration. Patients with schizophrenia did not show the expected habituation of motor activity. Selective genetic or pharmacologic inhibition of the dopamine transporter matched the mania phenotype better than the effects of amphetamine, which has been the criterion standard for animal models of mania.
These findings validate the human open field paradigm and identify defining characteristics of bipolar mania that are distinct from those of schizophrenia. This cross-species study of exploration calls into question an accepted animal model of mania and should help to develop more accurate human and animal models, which are essential to the identification of the neurobiological underpinnings of neuropsychiatric disorders.
Archives of general psychiatry 10/2009; 66(10):1072-80. · 12.26 Impact Factor
