Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2019

Open Access 01-12-2019 | Magnetic Resonance Imaging | Study protocol

The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS): study protocol for a randomised controlled, experimental medicine study

Authors: Lauren Z. Atkinson, Lucy Colbourne, Alexander Smith, Catherine H. Harmer, Anna C. Nobre, Jennifer Rendell, Helen Jones, Christopher Hinds, Arne Mould, Elizabeth M. Tunbridge, Andrea Cipriani, John R. Geddes, Kate E. A. Saunders, Paul J. Harrison

Published in: Trials | Issue 1/2019

Login to get access

Abstract

Background

The discovery that voltage-gated calcium channel genes such as CACNA1C are part of the aetiology of psychiatric disorders has rekindled interest in the therapeutic potential of L-type calcium channel (LTCC) antagonists. These drugs, licensed to treat hypertension and angina, have previously been used in bipolar disorder, but without clear results. Neither is much known about the broader effects of these drugs on the brain and behaviour.

Methods

The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS) is a high-intensity randomised, double-blind, placebo-controlled experimental medicine study on the effect of the LTCC antagonist nicardipine in healthy young adults with mood instability. An array of cognitive, psychiatric, circadian, physiological, biochemical and neuroimaging (functional magnetic resonance imaging and magnetoencephalography) parameters are measured during a 4-week period, with randomisation to drug or placebo on day 14. We are interested in whether nicardipine affects the stability of these measures, as well as its overall effects. Participants are genotyped for the CACNA1C risk polymorphism rs1006737.

Discussion

The results will clarify the potential of LTCC antagonists for repurposing or modification for use in psychiatric disorders in which cognition, mood and sleep are affected.

Trial registration

ISRCTN, ISRCTN33631053. Retrospectively registered on 8 June 2018 (applied 17 May 2018).
Appendix
Available only for authorised users
Literature
1.
Pazzaglia PJ, Post RM, Ketter TA, George MS, Marangell LB. Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation. Psychiatry Res. 1993;49:257–72.PubMedCrossRef
2.
Levy NA, Janicak PG. Calcium channel antagonists for the treatment of bipolar disorder. Bipolar Disord. 2000;2:108–19.PubMedCrossRef
3.
Warsh JJ, Andreopoulos S, Li PP. Role of intracellular calcium signaling in the pathophysiology and pharmacotherapy of bipolar disorder: current status. Clin Neurosci Res. 2004;4:201–13.CrossRef
4.
Wasserman MJ, Corson TW, Sibony D, Cooke RG, Parikh SV, Pennefather PS, et al. Chronic lithium treatment attenuates intracellular calcium mobilization. Neuropsychopharmacology. 2004;29:759–69.PubMedCrossRef
5.
Cipriani A, Saunders K, Attenburrow M-J, Stefaniak J, Panchal P, Stockton S, et al. A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development. Mol Psychiatry. 2016;21:1324–32.PubMedPubMedCentralCrossRef
6.
Heyes S, Pratt WS, Rees E, Dahimene S, Ferron L, Owen MJ, et al. Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders. Prog Neurobiol. 2015;134:36–54.PubMedPubMedCentralCrossRef
7.
8.
Zamponi GW, Striessnig J, Koschak A, Dolphin AC. The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Physiol Rev. 2015;67:821–70.
9.
10.
Hanyu H, Hirao K, Shimizu S, Iwamoto T, Kolzumi K, Abe K. Favourable effects of nilvadipine on cognitive function and regional cerebral blood flow on SPECT in hypertensive patients with mild cognitive impairment. Nucl Med Commun. 2007;28:281–7.PubMedCrossRef
11.
Tomassoni D, Lanari A, Silvestrelli G, Traini E, Amenta F. Nimodipine and its use in cerebrovascular disease: evidence from recent preclinical and controlled clinical studies. Clin Exp Hypertension. 2008;30:744–66.CrossRef
12.
Boal AH, Smith DJ, McCallum L, Muir S, Touyz RM, Dominiczak, et al. Monotherapy with major antihypertensive drug classes and risk of hospital admissions for mood disorders. Hypertension. 2016;68:1132–8.PubMedPubMedCentralCrossRef
13.
Dudley JA, Weir RK, Yan TC, Grabozska EM, Grimme AJ, Amini S, et al. Antagonism of L-type CaV channels with nifedipine differentially affects performance of wildtype and NK1R−/− mice in the 5-Choice Serial Reaction-Time Task. Neuropharmacology. 2013;64:329–36.PubMedCrossRef
14.
Levy A, Kong RM, Stillman MJ, Shukitthale B, Kadar T, Rauch TM, et al. Nimodipine improves spatial working memory and elevates hippocampal acetylcholine in young rats. Pharmacol Biochem Behav. 1991;39:781–6.PubMedCrossRef
15.
Quartermain D, DeSoria VG, Kwan A. Calcium channel antagonists enhance retention of passive avoidance and maze learning in mice. Neurobiol Learn Mem. 2001;75:77–90.PubMedCrossRef
16.
Quartermain D, Garcia DeSoria V. The effects of calcium channel antagonists on short- and long-term retention in mice using spontaneous alternation behavior. Neurobiol Learn Mem. 2001;76:117–24.PubMedCrossRef
17.
18.
Harrison PJ, Cipriani A, Harmer CJ, Nobre AC, Saunders K, Goodwin GM, et al. Innovative approaches to bipolar disorder and its treatment. Ann N Y Acad Sci. 2016;1366:76–89.PubMedPubMedCentralCrossRef
19.
McDonald KC, Saunders KEA, Geddes JR. Sleep problems and suicide associated with mood instability in the Adult Psychiatric Morbidity Survey, 2007. Aust N Z J Psychiatry. 2017;51:822–8.PubMedPubMedCentralCrossRef
20.
Amenta F, Tomassoni D, Traini E, Mignini F, Veglio F. Nicardipine: a hypotensive dihydropyridine-type calcium antagonist with a peculiar cerebrovascular profile. Clin Exp Hypertens. 2008;30:808–26.PubMedCrossRef
21.
Amenta F, Mignini F, Rabbia F, Tomassoni D, Veglio F. Protective effect of anti-hypertensive treatment on cognitive function in essential hypertension: analysis of published clinical data. J Neurol Sci. 2002;203:147–51.PubMedCrossRef
22.
Grotta J, Spydell J, Pettigrew C, Ostrow P, Hunter D. The effect of nicardipine on neuronal function following ischemia. Stroke. 1986;17:213–9.PubMedCrossRef
23.
Alps BJ, Calder C, Hass WK, Wilson AD. Comparative protective effects of nicardipine, flunarizine, lidoflazine and nimodipine against ischaemic injury in the hippocampus of the Mongolian gerbil. Br J Pharmacol. 1988;93:877–83.PubMedPubMedCentralCrossRef
24.
Gasior M, Kamiński R, Brudniak T, Kleinrok Z, Czuczwar SJ. Influence of nicardipine, nimodipine and flunarizine on the anticonvulsant efficacy of antiepileptics against pentylenetetrazol in mice. J Neural Transm. 1996;103:819–31.PubMedCrossRef
25.
Yamada S, Uchida S, Ohkura T, Kimura R, Yamaguchi M, Suzuki M, et al. Alterations in calcium antagonist receptors and calcium content in senescent brain and attenuation by nimodipine and nicardipine. J Pharmacol Exp Ther. 1996;277:721–7.PubMed
26.
Lin M, Aladejebi O, Hockerman GH. Distinct properties of amlodipine and nicardipine block of the voltage-dependent Ca(2+) channels Ca(v)1.2 and Ca(v)2.1 and the mutant channels Ca(v)1.2/dihydropyridine insensitive and Ca(v)2.1/dihydropyridine sensitive. Eur J Pharmacol. 2011;670:105–13.PubMedPubMedCentralCrossRef
27.
Sun WM, Edwards CA, Prior A, Rao SSC, Read NW. Effect of oral nicardipine on anorectal function in normal human volunteers and patients with irritable bowel syndrome. Dig Dis Sci. 1990;35:885–90.PubMedCrossRef
28.
Sheaves B, Porcheret K, Tsanas A, Espie CE, Foster RG, Freeman D, et al. Insomnia, nightmares, and chronotype as markers of risk for severe mental illness: results from a student population. Sleep. 2016;39:173–81.PubMedPubMedCentralCrossRef
29.
Hirschfeld RM, Williams JB, Spitzer RL, Calabrese JR, Flynn L, Keck PE, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. 2000;157:1873–5.PubMedCrossRef
30.
Hirschfeld RMA, Holzer C, Calabrese JR, Weissman M, Reed M, Davies M, et al. Validity of the mood disorder questionnaire: a general population study. Am J Psychiatry. 2003;160:178–80.PubMedCrossRef
31.
Zanarini MC, Vujanovic AA, Parachini EA, Boulanger JL, Frankenburg FR, et al. A screening measure for BPD: the McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD). J Personal Disord. 2003;17:568–73.CrossRef
32.
Horne J, Ostberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol. 1976;4:97–110.PubMed
33.
Espie CA, Kyle SD, Hames P, Gardani M, Fleming L, et al. The Sleep Condition Indicator: a clinical screening tool to evaluate insomnia disorder. BMJ Open. 2014;4:3.CrossRef
34.
35.
Finke K, Schwarzkopf W, Müller U, Frodl T, Muller HJ, Schneider WX, et al. Disentangling the adult attention-deficit hyperactivity disorder endophenotype: parametric measurement of attention. J Abnorm Psychol. 2011;120:890–901.PubMedCrossRef
36.
McAvinue LP, Habekost T, Johnson KA, Kyllingsbaek S, Vangkilde S, Bundesen C, et al. Sustained attention, attentional selectivity, and attentional capacity across the lifespan. Atten Percept Psychophys. 2012;74:1570–82.PubMedCrossRef
37.
McAvinue LP, Vangkilde S, Johnson KA, Habekost T, Kyllingsbaek S, Robertson IH, et al. The relationship between sustained attention, attentional selectivity, and capacity. J Cogn Psychol. 2012;24:313–28.CrossRef
38.
Habekost T. Clinical TVA-based studies: a general review. Front Psychol. 2015;6:1–18.CrossRef
39.
McAvinue LP, Vangkilde S, Johnson KA, Habekost T, Kyllingsbaek S, Bundesen C, et al. A componential analysis of visual attention in children with ADHD. J Atten Disord. 2015;19:882–94.PubMedCrossRef
40.
Harmer CJ, O’Sullivan U, Favaron E, Massey-Chase R, Ayres R, Reinecke A, et al. Effect of acute antidepressant administration on negative affective bias in depressed patients. Am J Psychiatry. 2009;166:1178–84.PubMedCrossRef
41.
Logan GD, Schachar RJ, Tannock R. Impulsivity and inhibitory control. Psychol Sci. 1997;8:60–4.CrossRef
42.
Strakowski SM, Fleck DE, DelBello MP, Adler CM, Shear PK, Kotwal R, et al. Impulsivity across the course of bipolar disorder. Bipolar Disord. 2010;12:285–97.PubMedPubMedCentralCrossRef
43.
Farrell SM, Tunbridge EM, Braeutigam S, Harrison PJ. COMT Val158Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition. Biol Psychiatry. 2012;71:538–44.PubMedPubMedCentralCrossRef
44.
Nelson HE, Willison J. National Adult Reading Test (NART). Windsor: NFER-Nelson; 1991.
45.
Chun MM, Jiang Y. Contextual cueing: implicit learning and memory of visual context guides spatial attention. Cogn Psychol. 1998;36:28–71.PubMedCrossRef
46.
Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol. 1988;54:1063–70.CrossRef
47.
Thompson ER. Development and validation of an internationally reliable short-form of the Positive and Negative Affect Schedule (PANAS). J Cross-Cult Psychol. 2007;38:227–42.CrossRef
48.
Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, et al. The 16-item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54:573–83.PubMedCrossRef
49.
Altman EG, Hedeker D, Peterson JL, Davis JM. The Altman Self-Rating Mania Scale. Biol Psychiatry. 1997;42:948–55.PubMedCrossRef
50.
Spitzer RL, Kroenke K, Williams JBW, Lowe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166:1092–7.PubMedCrossRef
51.
EuroQol. EuroQol - a new facility for the measurement of health-related quality of life. Health Policy (New York). 1990;16:199–208.CrossRef
52.
Carr O, Saunders KEA, Tsanas A, Bilderbeck AC, Palmius N, Geddes JR, et al. Variability in phase and amplitude of diurnal rhythms is related to variation of mood in bipolar and borderline personality disorder. Sci Rep. 2018;8:1–11.CrossRef
53.
Robert V, Triffaux E, Paulet PE, Guery JC, Pelletier L, Savignac M. Protein kinase C-dependent activation of CaV1.2 channels selectively controls human TH2-lymphocyte functions. J Allergy Clin Immunol. 2014;133:1175–83.PubMedCrossRef
54.
55.
Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016;21:1696–709.PubMedPubMedCentralCrossRef
56.
Wendt ER, Ferry H, Greaves DR, Keshav S. Ratiometric analysis of Fura Red by flow cytometry: a technique for monitoring intracellular calcium flux in primary cell subsets. PLOS One. 2015;10:e0119532.PubMedPubMedCentralCrossRef
57.
Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TEJ, Johansen-Berg H, et al. Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage. 2004;23:208–19.CrossRef
58.
59.
60.
Hoogenboom N, Schoffelen JM, Oostenveld R, et al. Localizing human visual gamma-band activity in frequency, time and space. Neuroimage. 2006;29:764–73.PubMedCrossRef
61.
Vidaurre D, Quinn AJ, Baker AP, Smith SM, Behrens T, Smith PJP, et al. Spectrally resolved fast transient brain states in electrophysiological data. NeuroImage. 2016;126:81–95.PubMedPubMedCentralCrossRef
62.
Saunders KEA, Cipriani A, Rendell J, Attenburrow M-J, Nelissen N, Bilderbeck AC, et al. Oxford Lithium Trial (OxLith) of the early affective, cognitive, neural and biochemical effects of lithium carbonate in bipolar disorder: study protocol for a randomised controlled trial. Trials. 2016;17:116.PubMedPubMedCentralCrossRef
63.
Schmidt JF, Waldemar G, Vorstrup S, Andersen AR, Gjebris F, Paulson OB. Computerized analysis of cerebral blood flow autoregulation in humans: validation of a method for pharmacologic studies. J Cardiovasc Pharmacol. 1990;15:983–8.PubMedCrossRef
64.
Canova D, Roatta S, Micieli G, Bosone D. Cerebral oxygenation and haemodynamic effects induced by nimodipine in healthy subjects. Funct Neurol. 2012;27:169–76.PubMed
65.
66.
Konrad-Dalhoff I, Baunnack AR, Rämsch KD, Ahr G, Kraft H, Schmitz H, et al. Effect of the calcium antagonists nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal motility in man. Eur J Clin Pharmacol. 1991;41:313–6.PubMedCrossRef
67.
Jones RI, Hornung RS, Sonecha T, Raftery EB. The effect of a new calcium channel blocker nicardipine on 24-hour ambulatory blood pressure and the pressor response to isometric and dynamic exercise. J Hypertens. 1983;1:85–9.PubMedCrossRef
68.
Yoshimizu T, Pan JQ, Mungenast AE, et al. Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons. Mol Psychiatry. 2015;20:162–9.PubMedCrossRef
69.
Ostacher MJ, Iosifescu DV, Hay A, Blumenthal SR, Sklar P, Perlis RH. Pilot investigation of isradipine in the treatment of bipolar depression motivated by genome-wide association. Bipolar Disord. 2014;16:199–203.PubMedCrossRef
70.
Gershon A, Eidelman P. Affective intensity and instability: predictors of depression and functional impairment in bipolar disorder. J Behav Ther Exp Psychiatry. 2015;46:14–8.PubMedCrossRef
71.
Tsanas A, Saunders K, Bilderbeck A, Palmius N, Goodwin G, De Vos M. Clinical insight into latent variables of psychiatric questionnaires for mood symptom self-assessment. JMIR Ment Health. 2017;4:e15.PubMedPubMedCentralCrossRef
72.
Sorkin EM, Clissold SP. Nicardipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in the treatment of angina pectoris, hypertension and related cardiovascular disorders. Drugs. 1987;33:296–345.PubMedCrossRef
Metadata
Title
The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS): study protocol for a randomised controlled, experimental medicine study
Authors
Lauren Z. Atkinson
Lucy Colbourne
Alexander Smith
Catherine H. Harmer
Anna C. Nobre
Jennifer Rendell
Helen Jones
Christopher Hinds
Arne Mould
Elizabeth M. Tunbridge
Andrea Cipriani
John R. Geddes
Kate E. A. Saunders
Paul J. Harrison
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Trials / Issue 1/2019
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-019-3175-0

Other articles of this Issue 1/2019

Trials 1/2019 Go to the issue

Research

Improving the relevance of randomised trials to primary care: a qualitative study investigating views towards pragmatic trials and the PRECIS-2 tool

Study protocol

Protective ventilation with high versus low positive end-expiratory pressure during one-lung ventilation for thoracic surgery (PROTHOR): study protocol for a randomized controlled trial

Study protocol

Using peer education to improve diabetes management and outcomes in a low-income setting: a randomized controlled trial

Review

Trials need participants but not their feedback? A scoping review of published papers on the measurement of participant experience of taking part in clinical trials

Study protocol

Anaesthetist-controlled versus patient-maintained effect-site targeted propofol sedation during elective primary lower-limb arthroplasty performed under spinal anaesthesia (ACCEPTS): study protocol for a parallel-group randomised comparison trial

Study protocol

Effect of motivational interviewing in hypertensive patients (MIdNIgHT): study protocol for a randomized controlled trial