Medication Adherence Failure in Schizophrenia: a Forensic Review of Rates, Reasons, Treatments, and Prospects

Total Page:16

File Type:pdf, Size:1020Kb

Medication Adherence Failure in Schizophrenia: a Forensic Review of Rates, Reasons, Treatments, and Prospects Medication Adherence Failure in Schizophrenia: A Forensic Review of Rates, Reasons, Treatments, and Prospects John L. Young, MD, Reuben T. Spitz, PhD, Marc Hillbrand, PhD, and George Daneri, MSN Forensic patients with schizophrenia who fail to adhere to prescribed antipsy- chotic medication risk recidivism, which continues to be a serious concern. It affects all stages of trial proceedings and impacts on the treaters' liability. Al- though much remains unchanged since the authors reviewed the subject in 1986, significant advances have occurred. A patient's insight can be assessed with greater precision. Risks posed by past noncompliance, substance abuse, and a dysphoric response to medication are more clearly documented. Clinical and laboratory methods for assessing compliance have improved. Major advances in the effective amelioration of adverse effects can be applied to promote adherence. New augmentation strategies enable adequate treatment at lower doses. The development of atypical antipsychotic agents makes compliance easier to achieve and maintain. Other advances apply to the containment of relapse when it does occur. This review organizes the literature documenting these trends for use in both treatment and consultation. Recent advances in the treatment of schizo- with its potential for relapse and recidivism phrenia have so far not improved adherence has not changed over the 12 years since this to treatment nor have they decreased the subject was updated under a forensic codi- public's concern about the violence of some fication.' At the same - time, notable patients with this disorder. In fact, the re- progress in the understanding and treatment ported risk of medication noncompliance of schizophrenia has produced develop- ments hlghly relevant to the problems of The authors are affiliated with the Whiting Forensic Division of Connecticut Valley Hospital, Middletown, noncompliance and relapse. The purpose of CT. Drs. Young and Hillbrand are also affiliated with this update is to organize and present this the Yale University School of Medicine, New Haven, CT. Dr. Spitz is affiliated with the Albert Einstein Col- information for the use of those who treat lege of Medicine, Bronx, NY. An earlier version of this forensic patients with schizophrenia and paper was presented at the 27th annual meeting of the American Academy of Psychiatry and the Law, October, consult on the issue of potential dangerous- 1996, San Juan, PR. Address correspondence to: John L. Young, MD, Box 70, Middletown, CT 06457. E-mail ness arising from relapse following nonad- address: [email protected] herence to prescribed medication. 426 J Am Acad Psychiatry Law, Vol. 27, No. 3, 1999 Medication Adherence Failure This review provides information that compliance rates for all of medicine con- applies to both criminal and civil pro- tinue to be approximately 50 percent; the ceedings. Medication compliance influ- usual methods for measuring compliance ences the handling of pretrial matters are interviews, pill counts, and assays such as diversion programs, bail negotia- based on the drug or a marker; and clini- tions, restorations of competency to stand cians persist in blaming the patient for trial, plea bargains, and applications for default. Treaters also remain poor predic- accelerated rehabilitation. After trial, tors of their own patients' default rates." medication compliance is salient to dis- The many forms of compliance failure cussions of alternatives to incarceration, continue to include the following: inade- sentence modification, parole application, quate engagement in the treatment rela- and the management of insanity acquit- tionship after accepting a referral, re- tees. Deliberations about the prospect of peated missed appointments, ignoring or noncompliance leading to dangerousness misinterpreting instructions or adjusting or grave disability dominate civil cornmit- the medication regimen independently, ment proceedings. The issue continues to and abrupt termination of treatment.'' be of concern in connection with efforts to Since failure to comply with depot (long- assure patients' rights and their informed acting injectable) medications is readily consent to proposed medication regimens. recognizable, noncompliance with oral Most applications for the information medications retains the primary focus. In presented here are not new. Liability for accordance with continuing concern alleged negligent release is the major ex- about undue blaming of the patient, there ~eption.~This trend is especially worr- is a growing consensus on the value of some because of the decreasing length of reformulating the usage of compliance in inpatient stays and its correlation with terms of adherence, thereby acknowledg- early relap~e,~along with significant ero- ing that compliance includes participation sion of protections from such liabilit~.~ in an alliance with shared responsibility Also new is a trend favoring prearraign- for effective collaboration. " ment diversion programs. These pro- Most authors, continuing to report grams offer courts the option of an im- medication default across a broad spec- mediate referral to treatment for patients trum, use a definition based on clinical recognized to be in relapse5 and have significance. The present review, based been shown to expedite proceeding^.^ To on targeted reading of refereed journals respond to some cases, prosecutors will supplemented by literature searches cov- need expert opinion on the prognosis for ering the years 1986 through 1997, gen- ~ompliance.~ erated a total of 34 reports.'- 12-4 Table 1 summarizes the results for oral medica- Definition and Extent of tion; 35 default measurements in 29 re- Noncompliance ports show a median default rate of 46 The basic landmarks remain un- percent, ranging from 5 to 85 percent. changed since our 1986 review: general Table 2 shows the same information for J Am Acad Psychiatry Law, Vol. 27, No. 3, 1999 427 Table 1 Results Reoorted from Investigations of Outpatient Oral Medication Compliance % Default Reference Rate (N) Subiects Observation Period Method of Detection Casper and Regani2 Newly admitted recidivists Single point Nurse rating Fernando et a1.I3 Discharged patients Up to one year Patient interview Drake et aLi4 Rural outpatients, unstable One year Patient interview, clinician housing rating Razali and Yahyai5 Readmitted patients Two weeks Questionnaires Casperi6 Patients admitted three or more Three years Patient interview, record times within 18 months review Kashner eta/.'? Random Veterans Affairs-admitted Single point Record review patients Giron and Gomez- Discharged patients Two years Self- and relatives' reports Beneytoi8 Adams and Howeig Newly admitted patients One month Interview of patient Casperi6 Patients admitted fewer than three Three years Patient interview, record times within 18 months review Hicks2' Readmitted patients Up to one year Patient interview Frank and Psychotherapy patients Six months Patient and therapist reports; G~nderson~~ record review Smoot et Readmitted patients Single point Patient interview Kelly et Discharged veterans Available past history Record review Awad and Hogan24 Clinic outpatients Single point Therapist rating Weiden and glaze^.'^ Newly readmitted high utilizers Single point Assessment by admitting team McEvoy et Discharged prior noncompliers Four to 42 months Records, clinician interviews cO Nageotte et aL2' Readmitted patients Three years Self- and relatives' reports !!= 3 Scottish Schizophrenia First episode inpatients Five weeks Radioimmunoassay of serum v, z. Research Gro~p*~ F Jenkins et Discharged patients Nine months Record review Eckman et Outpatient study volunteers Single point Caregiver rating -I Kapur et a/.' Day hospital patients Three months Riboflavin urine marker Opler et Homeless indigent men Single point Self-report sZI P Davidhizar et Newly admitted patients Single point Record review Eckman et Outpatient study volunteers Single point Psychiatrist rating !? Table 1 z Continued p. 0 % Default % 0 Reference Rate (N) Subjects Observation Period Method of Detection 3 D B~chanan~~ 32 (19/59) Patients two years after discharge Single point Records, urine tests Q McFarland et 27 (591215) Outpatients Single point Questionnaire mailed to relatives Weiden et 26 (14153) Discharged patients One month Multiple interviews, records 32 B~chanan~~ 25 (15161) Patients one year after discharge Single point Records, urine tests o(D McEvoy et 25 (9136) Discharged prior noncompliers One month Records, clinician interviews n Drake et a1.14 23 (13/56) Rural outpatients, stable housing One year Patient interview, clinician rating Opler et 18 (18/100) Never homeless indigent men Single point Self-report 5 Sellwood and Tarrier36 17 (431256) Discharged patients Up to three years Psychiatrist interview Pablo et 15 (2311 50) Readmitted patients Single point Record review Owen et 15 (2011 30) Inpatients Two one-month Self-report, informants periods six months apart Hazel et 5 (10011,992) Clinic outpatients Single point Clinician assessment Table 2 Results Reported from Investigations of Outpatient Depot Medication Compliance Reference Default Rate % (N) Subjects Observation Period Method of Detection Bartko et 54 (30156) Discharged patients One year Appointment record Soni et 48 (42188) Medication clinic patients Up to five years Observation Tunnicliffe et 21 (18184) Medication clinic patients One year Record review Hogarty et 17 (12170) Consecutive admissions Two years Record study Pan and Tantam44
Recommended publications
  • Monoamine Depletion in Psychiatric and Healthy Populations
    Molecular Psychiatry (2003) 8, 951–973 & 2003 Nature Publishing Group All rights reserved 1359-4184/03 $25.00 www.nature.com/mp FEATURE REVIEW Monoamine depletion in psychiatric and healthy populations: review L Booij1, AJW Van der Does1,2 and WJ Riedel3,4,5 1Department of Psychology, Leiden University, Leiden 2333 AK, The Netherlands; 2Department of Psychiatry, Leiden University, Leiden 2333 AK, The Netherlands; 3GlaxoSmithKline, Translational Medicine & Technology, Cambridge, UK; 4Department of Psychiatry, University of Cambridge, UK; 5Faculty of Psychology, Maastricht University, The Netherlands A number of techniques temporarily lower the functioning of monoamines: acute tryptophan depletion (ATD), alpha-methyl-para-tyrosine (AMPT) and acute phenylalanine/tyrosine deple- tion (APTD). This paper reviews the results of monoamine depletion studies in humans for the period 1966 until December 2002. The evidence suggests that all three interventions are specific, in terms of their short-term effects on one or two neurotransmitter systems, rather than on brain protein metabolism in general. The AMPT procedure is somewhat less specific, affecting both the dopamine and norepinephrine systems. The behavioral effects of ATD and AMPT are remarkably similar. Neither procedure has an immediate effect on the symptoms of depressed patients; however, both induce transient depressive symptoms in some remitted depressed patients. The magnitude of the effects, response rate and quality of response are also comparable. APTD has not been studied in recovered major depressive patients. Despite the similarities, the effects are distinctive in that ATD affects a subgroup of recently remitted patients treated with serotonergic medications, whereas AMPT affects recently remitted patients treated with noradrenergic medications.
    [Show full text]
  • The Effects of Clonidine and Idazoxan on Cerebral Blood Flow in Rats Studied by Arterial Spin Labeling Magnetic Resonance Perfusion Imaging
    The Effects of Clonidine and Idazoxan on Cerebral Blood Flow in Rats Studied by Arterial Spin Labeling Magnetic Resonance Perfusion Imaging X. Du1, H. Lei1 1State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics & Mathematics, Chinese Academy of Sciences, Wuhan, Hubei, China, People's Republic of Introduction Agonists of α2-adrenoceptors are known to produce many central and peripheral effects. For example, xylazine, a selective α2-adrenoceptors agonist, has been shown to cause region-dependent CBF decreases in rat [1]. Clonidine, an agonist for both α2-adrenergic receptor and imidazoline receptor, is a widely used drug for treating hypertension. Its effect on CBF, however, is not well understood. In this study, continuous arterial labeling (CASL) MR perfusion imaging was used to investigate the effects of clonidine and idazoxan, an antagonist for α2-adrenergic and imidazoline receptors, on CBF in rats. Materials and Methods Twelve male Sprague-Dawley rats, weighting 250-320 g, were used. After intubation, the rats were anesthetized by 1.0-1.5% isoflurane in a 70:30 N2O/O2 gas mixture. For each rat, bilateral femoral arteries and the right femoral vein were catheterized for monitoring blood gases and blood pressure, and for delivering drugs. Rectal temperature was maintained at 37.0-37.5 oC using a warm water pad. After measuring baseline CBF, the rats were divided into two groups. In the first group (n=7), clonidine (10 µg/kg, i.v.) was injected first, followed by idazoxan injection (300 µg/kg, i.v.) at 30 minutes later. Perfusion maps were obtained after administration of each drug.
    [Show full text]
  • Dopamine D2 Receptors in the Cerebral Cortex
    Proc. Nati. Acad. Sci. USA Vol. 86, pp. 6412-6416, August 1989 Neurobiology Dopamine D2 receptors in the cerebral cortex: Distribution and pharmacological characterization with [3Hlraclopride (raclopride binding/neostriatum/rat/monkey) MICHAEL S. LIDOW*t, PATRICIA S. GOLDMAN-RAKIC*, PASKO RAKIC*, AND ROBERT B. INNIS*f Section of *Neuroanatomy and tDepartment of Psychiatry, Yale University, School of Medicine, New Haven, CT 06510 Contributed by Pasko Rakic, May 17, 1989 ABSTRACT An apparent involvement of dopamine in the MATERIALS AND METHODS regulation of cognitive functions and the recognition of a widespread dopaminergic innervation of the cortex have fo- Tissue was obtained from three adult rhesus monkeys cused attention on the identity of cortical dopamine receptors. (Macaca mulatta): one male and two females. The animals However, only the presence and distribution of dopamine DI were anesthesized with sodium pentobarbital (40 mg/kg) and receptors in the cortex have been well documented. Compa- perfused with ice-cold phosphate-buffered saline followed by rable information on cortical D2 sites is lacking. We report here 0.1% paraformaldehyde (9; 15). The cerebral cortex and the results of binding studies in the cortex and neostriatum of neostriatum were rapidly removed and immersed in isopen- rat and monkey using the D2 selective antagonist [3H]raclo- tane at -700C for 5 min before storing at -800C until use. For pride. In both structures [3H]raclopride bound in a sodium- competition studies tissue was pooled from several neocor- dependent and saturable manner to a single population of sites tical areas. However, saturation studies were conducted on with pharmacological profiles of dopamine D2 receptors.
    [Show full text]
  • Psychosis and Schizophrenia in Clinical Practice Psychosis in Practice
    11/1/2017 Psychosis and Schizophrenia in Clinical Practice David Pickar, MD Adjunct Professor Johns Hopkins USUHS Psychosis in Practice • Schizophrenia • Mania • Depression • Brief Psychotic Episodes • Substance Abuse • FASD and other Neurodevelopment Disorders 1 11/1/2017 Schizophrenia • Late Adolescent/Early Adult Age of Onset • Life-Long Condition and Chronic Medication – Typical Antipsychotic drugs – introduced in 50’s -60’s – Atypical Antipsychotic drugs – introduced in later 80’s 90’s – Clozapine is the only ADP with demonstrated superiority – Market For Antipsychotic Drugs : Peak $16B /year US • 1% of World Population • Common “Complex” Disorder – Pathophysiology – Genetics – Variable Phenotype • Positive and Negative Symptoms and Cognitive Deficits • 10% Completed Suicide Prevalence and Treatment Rates • 8.1 million adults with schizophrenia or bipolar disorder mental illness (3.3% of the population)+ • 5.4 million – approximate number with severe bipolar disorder (2.2% of the population), 51% untreated+ • 2.7 million – approximate number with schizophrenia (1.1% of the population), 40% untreated+ • 3.9 million – approximate number untreated seriously mentally ill patients in any given year (1.6% of the population)+ 2 11/1/2017 Positive and Negative Symptom Scale (PANSS) Positive Symptoms • 7 Items, (minimum score = 7, maximum score = 49) • Delusions • Conceptual disorganization • Hallucinations • Excitement • Grandiosity • Suspiciousness/persecution • Hostility 3 11/1/2017 PANSS Negative Symptoms • 7 Items, (minimum score = 7,
    [Show full text]
  • Cocaine and Amphetamine Interact at 5HT Synapses Through Distinct Mechanisms in Guinea-Pig Prepositus Hypoglossi
    The Journal of Neuroscience, July 1991, 17(7): 2151-2156 Cocaine and Amphetamine Interact at 5HT Synapses through Distinct Mechanisms in Guinea-pig Prepositus Hypoglossi Daniel H. Bobker and John T. Williams Vellum Institute, Oregon Health Sciences University, Portland, Oregon 97201 Intracellular recordings were made from guinea-pig prepos- two compounds have reinforcing properties in behavioral par- itus hypoglossi (PH) neurons in vitro. Neurons within this adigms (Wise, 1984), and appear to act primarily through mono- nucleus are innervated by terminals that release 5-HT (se- aminergic systems. Cocaine is a potent monoamine uptake in- rotonin) to mediate an IPSP. Cocaine caused a concentra- hibitor (Ross and Renyi, 1967, 1969), and its reinforcing tion-dependent prolongation of that IPSP, while having no properties correlate well with its affinity for the dopamine trans- effect on either membrane potential or firing rate. Cocaine porter (Ritz et al., 1987). Amphetamine is a relatively weaker also caused an increase in the IPSP amplitude at lower con- uptake inhibitor, but it also has monoamine-releasing effects centrations (5 1 PM) and a decrease at higher concentra- and direct agonist actions at some receptors (Homan and Ziance, tions. The selective 5-HT uptake inhibitor fluoxetine also 198 1; Ritz and Kuhar, 1989). The self-administration of am- prolonged the IPSP duration but depressed the amplitude at phetamine and related analogs does not correlate with their all concentrations tested. The effects of cocaine on IPSP affinity for the dopamine transporter, but may correlate nega- duration can be completely accounted for by inhibition of tively with the affinity for the 5-HT transporter (Ritz and Kuhar, 5-HT uptake.
    [Show full text]
  • Sustained Administration of Pramipexole Modifies the Spontaneous Firing of Dopamine, Norepinephrine, and Serotonin Neurons in the Rat Brain
    Neuropsychopharmacology (2009) 34, 651–661 & 2009 Nature Publishing Group All rights reserved 0893-133X/09 $32.00 www.neuropsychopharmacology.org Sustained Administration of Pramipexole Modifies the Spontaneous Firing of Dopamine, Norepinephrine, and Serotonin Neurons in the Rat Brain ,1 1 1,2 O Chernoloz* , M El Mansari and P Blier 1 2 Institute of Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada Pramipexole (PPX) is a D2/D3 receptor agonist that has been shown to be effective in the treatment of depression. Serotonin (5-HT), norepinephrine (NE) and dopamine (DA) systems are known to be involved in the pathophysiology and treatment of depression. Due to reciprocal interactions between these neuronal systems, drugs selectively targeting one system-specific receptor can indirectly modify the firing activity of neurons that contribute to firing patterns in systems that operate via different neurotransmitters. It was thus hypothesized that PPX would alter the firing rate of DA, NE and 5-HT neurons. To test this hypothesis, electrophysiological experiments were carried out in anesthetized rats. Subcutaneously implanted osmotic minipumps delivered PPX at a dose of 1 mg/kg per day for 2 or 14 days. After a 2-day treatment with PPX the spontaneous neuronal firing of DA neurons was decreased by 40%, NE neuronal firing by 33% and the firing rate of 5-HT neurons remained unaltered. After 14 days of PPX treatment, the firing rate of DA had recovered as well as that of NE, whereas the firing rate of 5-HT neurons was increased by 38%.
    [Show full text]
  • (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 1: Background and Methods of the Development of Guidelines Konstantinos N
    Copyedited by: oup International Journal of Neuropsychopharmacology (2017) 20(2): 95–97 doi:10.1093/ijnp/pyx002 Editorial EDITORIAL Treatment Guidelines in Bipolar Disorders and the Importance of Proper Clinical Trial Design Mauricio Tohen Department of Psychiatry & Behavioral Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. Correspondence: Mauricio Tohen, MD, DrPH, MBA, Department of Psychiatry & Behavioral Sciences, University of New Mexico Health Sciences Center, 2400 Tucker Ave, Albuquerque, NM 87131, USA ([email protected]). A working group led by Dr. Konstantinos Fountoulakis developed (http://clinicaltrials.gov and http://www.clinicalstudyresults. the first International College of Neuropsychopharmacology org) as well as web pages of pharmaceutical companies with (CINP) clinical guidelines for the treatment of Bipolar Disorders compounds used in bipolar disorder up to March 25, 2016. in adult patients. Their work is very thoroughly described in The authors provide a critical analysis of the existing treat- four separate papers (parts) included in this issue of the journal. ment grading methods that led them to determine that there The first article is Background and Methods of the Development was no optimal method to grade treatments for bipolar disorder, of Guidelines (Fountoulakis et al., 2017d); part 2 is Review, therefore creating their own grading system. Their methodology Grading of the Evidence, and a Precise Algorithm (Fountoulakis provides 32 different levels of recommendations, starting with et al., 2017c); part 3 is The Clinical Guidelines (Fountoulakis the optimal: “At least 1 positive 2 active arm RCT vs placebo et al., 2017a); and Part 4 is Unmet Needs in the Treatment of exists, plus positive 1 active arm RCTs, and no negative RCTs.” Bipolar Disorder and Recommendations for Future Research Lower level scenarios take into account posthoc reports, meta- (Fountoulakis et al., 2017b).
    [Show full text]
  • Assessment Report
    31 May 2018 EMA/556923/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report RXULTI International non-proprietary name: brexpiprazole Procedure No. EMEA/H/C/003841/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2018. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier ..................................................................................... 8 1.2. Steps taken for the assessment of the product ........................................................ 9 2. Scientific discussion .............................................................................. 10 2.1. Problem statement ............................................................................................. 10 2.1.1. Disease or condition ........................................................................................ 10 2.1.2. Epidemiology and risk factors, screening tools/prevention .................................... 10 2.1.3. Biologic features, aetiology and pathogenesis ..................................................... 10 2.1.4. Clinical presentation, diagnosis
    [Show full text]
  • (C) Hit Agreement Between Seeding Densities
    (a) Morphological space (b) Identification of hits (c) Hit agreement between 1500 cells per well 1500 cells per well seeding densities DMSO 8 1.00 Pentamidine 1.00 Wiskostatin Hydroxychloroquine Imatinib 0.75 0.75 4 Gefitinib Compound DMSO Pentamidine 0.50 0.50 0 Vinblastine UMAP2 Wiskostatin Vinblastine 0.25 0.25 Vinblastine −4 Plate at 1500 cells/well Robust Hellinger Distance Wiskostatin Pentamidine 0.00 DMSO 0.00 −4 0 4 0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00 UMAP1 FDR−corrected p−value Plate at 750 cells/well Supp. Figure 1: BioProfiling.jl profiles of plates seeded at 750 and 1500 cells per well curated with are similar. (a) UMAP embedding preserving the cosine distance between the mor-phological profiles aggregated per field of view in the plate seeded with 1500 cells per well. Two out of four dimensions are represented. (b) Robust Hellinger distance and Ro-bust Morphological Perturbation Value (FDR-corrected p-value) of each compound in the plate seeded with 1500 cells per well compared to DMSO. Vertical dotted line indicates an FDR threshold of 0.1 and all compounds on its left are defined as morphological hits. (c) FDR-corrected p-value of the significance of morphological changes induced by each compound in both plates. Dotted lines indicate an FDR threshold of 0.1. CompoundName MOA Targets RMPV750 RMPV1500 (+)-Butaclamol hydrochloride 0.2479179 0 (+)-Cyclazocine 0.0288018 0.0012478 ["ABCC1", "ABCC2", "FPR1", (+/-)-Sulfinpyrazone ["Uricosuric blocker"] "SLC22A12"] 0.0019172 0.015413 (-)-JQ1 0.0003682 0 (-)-Perillic
    [Show full text]
  • Comparative Exploration of the Structure–Activity Space of Cloned A-Like Octopamine Receptors from a Marine and a Terrestrial Arthropod S
    Supplemental material to this article can be found at: http://molpharm.aspetjournals.org/content/suppl/2017/06/29/mol.117.108456.DC1 1521-0111/92/3/297–309$25.00 https://doi.org/10.1124/mol.117.108456 MOLECULAR PHARMACOLOGY Mol Pharmacol 92:297–309, September 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics Comparative Exploration of the Structure–Activity Space of Cloned a-Like Octopamine Receptors from a Marine and a Terrestrial Arthropod s Dhwanil A. Dalwadi and John A. Schetz Department of Pharmacology and Neuroscience (D.A.D., J.A.S.), Graduate School of Biomedical Sciences, Institute for Healthy Aging, Center for Neuroscience Discovery, and Department of Medical Education (J.A.S.), Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, Texas Received January 23, 2017; accepted June 26, 2017 Downloaded from ABSTRACT The a-like octopamine receptors (OctR) are believed to be the different mechanisms of action. For instance, significant differ- evolutionary precursor to the vertebrate a2-adrenergic receptors ences in the efficacy for some agonists were observed, includ- (a2-ARs) based upon sequence similarity and the ability to ing that vertebrate biogenic amines structurally related to interact with norepinephrine and a number of compounds that octopamine acted as superagonists at the DmOctR but partial molpharm.aspetjournals.org bind with high affinity to a2-ARs. Barnacles and fruit flies are agonists at the BiOctR, and the two species diverged in their 3 two prominent model marine and terrestrial representatives of sensitivities to the a2-AR antagonist [ H]rauwolscine.
    [Show full text]
  • The A2-Adrenoceptor Antagonist Idazoxan Reverses Catalepsy Induced by Haloperidol in Rats Independent of Striatal Dopamine Release: Role of Serotonergic Mechanisms
    Neuropsychopharmacology (2003) 28, 872–879 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org The a2-Adrenoceptor Antagonist Idazoxan Reverses Catalepsy Induced by Haloperidol in Rats Independent of Striatal Dopamine Release: Role of Serotonergic Mechanisms ,1 1 {,1 Roberto W Invernizzi* , Claudio Garavaglia and Rosario Samanin 1Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milano, Italy The a -adrenoceptor antagonist idazoxan may improve motor symptoms in Parkinson’s disease and experimental Parkinsonism. We 2 studied the effect of idazoxan on haloperidol-induced catalepsy in rats, an animal model of the drug-induced extrapyramidal side effects in man. Catalepsy was induced by a subcutaneous (s.c.) injection of haloperidol (1 mg/kg) and measured by the bar test for a maximum of 5 min. At 3 h after haloperidol, rats were given 0.16–5.0 mg/kg s.c. idazoxan, and descent latency was measured 1 h later. Idazoxan potently reversed haloperidol-induced catalepsy with an ED50 of 0.25 mg/kg. This effect was mimicked by the selective a2-adrenoceptor antagonist RS-15385-197 (0.3 and 1 mg/kg orally). We assessed how dopaminergic mechanisms were involved in the anticataleptic effect of idazoxan by studying its effect on dopamine (DA) release in the striatum, with the microdialysis technique in conscious rats. Idazoxan (0.3 and 2.5 mg/kg) had no effect on extracellular DA and did not modify the rise of extracellular DA induced by haloperidol, indicating that changes of striatal DA release were not involved in the reversal of catalepsy. The anticataleptic effect of 2.5 mg/kg idazoxan (haloperidol+vehicle 288 7 8 s, haloperidol+idazoxan 47 7 22 s) was attenuated in rats given an intraventricular injection of 150 mgof the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (haloperidol+vehicle 275 7 25 s, haloperidol+idazoxan 137 7 28 s).
    [Show full text]
  • (M-CPP) Induced Intracavernous Pressure Responses in Anaesthetized Rats
    International Journal of Impotence Research (2002) 14, 287–294 ß 2002 Nature Publishing Group All rights reserved 0955-9930/02 $25.00 www.nature.com/ijir Metachlorophenylpiperazine (m-CPP) induced intracavernous pressure responses in anaesthetized rats ES Hayes1* and PG Adaikan1 1Department of Obstetrics and Gynaecology, the National University of Singapore, Singapore Here we have recorded the effects of metachlorophenylpiperazine (m-CPP) on intracavernous pressure (ICP) in anesthetized rats pretreated with various pharmacological agents in an attempt to determine the mechanism and relevance of the m-CPP induced ICP response to other models of erection. m-CPP elicited consistent and significantly greater increases in ICP (71.5 Æ 6.6 mmHg) compared with the mixed 5-HT2a=2c agonists trifluoromethylphenylpiperazine (3.4 Æ 1.3 mmHg) and quipazine (10.9 Æ 1.8 mmHg). Blockade of 5-HT2a receptors with ketanserin failed to unmask any stimulatory effect of quipazine (7.2 Æ 1.0 mmHg). m-CPP induced ICP responses (71 Æ 7.0 mmHg) were unaffected in the presence of mianserin (63 Æ 5 mmHg) and ketanserin (51 Æ 12 mmHg). Spiperone significantly reduced the m-CPP induced increase in ICP (8.0 Æ 1.0 mmHg). Naloxone, yohimbine and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) failed to elicit increases in ICP on their own. All three drugs significantly reduced the latency to the first m-CPP induced ICP response compared to saline. Yohimbine increased the duration of m- CPP induced ICP responses whereas 8-OHDPAT increased the mean number of m-CPP induced ICP responses compared to saline.
    [Show full text]