Concomitant Calcium Channel Blocker and Antipsychotic Therapy in Patients with Schizophrenia: Efficacy Analysis of the Catie-Sz Phase 1 Data

Abstract

Background

This study evaluated the influence of concomitant calcium channel blocker (CCB) and antipsychotic (AP) therapy on efficacy measures in patients with schizophrenia.

Methods

Data from the Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia study were used to evaluate the effect of concomitant CCB therapy on the Clinical Global Impression-Severity (CGI-S) score, Positive and Negative Syndrome Scale (PANSS) score, and time to all-cause discontinuation of AP treatment. Concomitant treatment participants (CCB plus AP) were matched with controls (AP alone) by propensity scores using a 3:1 greedy match algorithm, then analyzed using a mixed linear effects model adjusted for fixed covariates.

Results

The least squares mean change in CGI-S scores revealed a significant time-by-treatment interaction term, with greater improvements for the concomitant treatment group (P = .03). Total PANSS score showed no significant difference between groups at various time periods (1, 3, 6, 9, 12, 15, and 18 months) and time to all-cause discontinuation was also similar (hazard ratio 0.94, P = .73).

Conclusions

Improvements in CGI-S scores over time suggest that concomitant CCB plus AP treatment may reduce severity of illness more than AP treatment alone. However, PANSS score and time to all-cause discontinuation of AP treatment did not demonstrate improved outcomes.

Get full access to this article

View all access options for this article.

References

Lieberman

Stroup

Perkins

. The American Psychiatric Publishing textbook of schizophrenia. Arlington, VA: American Psychiatric Publishing, Inc; 2006.

Rossler

Salize

van Os

, . Size of burden of schizophrenia and psychotic disorders. Eur Neuropsychopharmacol. 2005;15:399–409.

Sullivan

Kendler

Neale

. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60:1187–1192.

Hamshere

Walters

Smith

; Schizophrenia Psychiatric Genome-wide Association Study Consortium; Wellcome Trust Case Control Consortium+; Wellcome Trust Case Control Consortium 2. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Mol Psychiatry. 2013;18:708–712.

Liao

Soong

. CaV1.2 channelopathies: from arrhythmias to autism, bipolar disorder, and immunodeficiency. Pflugers Arch. 2010;460:353–359.

Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–427.

Ripke

O'Dushlaine

Chambert

; Multicenter Genetic Studies of Schizophrenia Consortium; Psychosis Endophenotypes International Consortium; Wellcome Trust Case Control Consortium 2. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45:1150–1159.

Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43:969–976.

Jiang

Qiao

. Evaluating the association between CACNA1C rs1006737 and schizophrenia risk: a meta-analysis. Asia Pac Psychiatry. 2015;7:260–267.

10.

Porcelli

Lee

Han

. CACNA1C gene and schizophrenia: a case-control and pharmacogenetic study. Psychiatr Genet. 2015;25:163–167.

11.

Nyegaard

Demontis

Foldager

. CACNA1C (rs1006737) is associated with schizophrenia. Mol Psychiatry. 2010;15:119–121.

12.

Ortner

Striessnig

L-type calcium channels as drug targets in CNS disorders. Channels (Austin). 2016;10:7–13.

13.

Berger

Bartsch

The role of L-type voltagegated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function. Cell Tissue Res. 2014;357:463–476.

14.

Imbrici

Camerino

Tricarico

Major channels involved in neuropsychiatric disorders and therapeutic perspectives. Front Genet. 2013;4:76.

15.

Kabir

Lee

Rajadhyaksha

. L-type Ca2+ channels in mood, cognition and addiction: integrating human and rodent studies with a focus on behavioural endophenotypes. J Physiol. 2016;594:5823–5837.

16.

Bloom

Tourjman

Nair

. Verapamil in refractory schizophrenia: a case report. Prog Neuropsychopharmacol Biol Psychiatry. 1987;11: 185–188.

17.

Bartko

Horvath

Zador

. Effects of adjunctive verapamil administration in chronic schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry. 1991;15:343–349.

18.

Price

. Antipsychotic effects of verapamil in schizophrenia. Hillside J Clin Psychiatry. 1987;9:225–230.

19.

Grebb

Shelton

Taylor

. A negative, double-blind, placebo-controlled, clinical trial of verapamil in chronic schizophrenia. Biol Psychiatry. 1986;21:691–694.

20.

Uhr

Jackson

Berger

. Effects of verapamil administration on negative symptoms of chronic schizophrenia. Psychiatry Res. 1988;23: 351–352.

21.

Stedman

Whiteford

Eyles

. Effects of nifedipine on psychosis and tardive dyskinesia in schizophrenic patients. J Clin Psychopharmacol. 1991;11:43–47.

22.

Schwartz

Fay-McCarthy

Kendrick

. Effects of nifedipine, a calcium channel antagonist, on cognitive function in schizophrenic patients with tardive dyskinesia. Clin Neuropharmacol. 1997; 20:364–370.

23.

Suddath

Straw

Freed

. A clinical trial of nifedipine in schizophrenia and tardive dyskinesia. Pharmacol Biochem Behav. 1991;39:743–745.

24.

Garza-Trevino

Overall

Hollister

. Verapamil versus lithium in acute mania. Am J Psychiatry. 1992;149:121–122.

25.

Mallinger

Thase

Haskett

. Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms. Bipolar Disord. 2008;10:856–866.

26.

Nimmrich

Eckert

Calcium channel blockers and dementia. Br J Pharmacol. 2013;169:1203–1210.

27.

Silverstone

Birkett

Diltiazem as augmentation therapy in patients with treatment-resistant bipolar disorder: a retrospective study. J Psychiatry Neurosci. 2000;25:276–280.

28.

Lieberman

Stroup

McEvoy JP; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–1223.

29.

Stroup

Lieberman

. Antipsychotic trials in schizophrenia: the CATIE project. New York, NY: Cambridge University Press; 2010.

30.

van Buuren

, Groothuis-Oudshoorn

CGM

. mice: Multivariate imputation by chained equations in R. J Stat Soft. 2011;45:1–67.

31.

Rosenbaum

Rubin

. The central role of propensity score in observational studies for casual effects. Biometrika. 1983;70:41–55.

32.

Imai

King

. MatchIt: nonparametric preprocessing for parametric casual inference. J Stat Soft. 2011;42:1–28.

33.

Busner

Targum

. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry (Edgmont). 2007;4:28–37.

34.

Kay

Fiszbein

Opler

. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13:261–276.

35.

Chobanian

; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560–2572.

36.

Yoshimizu

Pan

Mungenast

. Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons. Mol Psychiatry. 2015;20:162–169.

37.

Bonci

Grillner

Mercuri

. L-type calcium channels mediate a slow excitatory synaptic transmission in rat midbrain dopaminergic neurons. J Neurosci. 1998;18:6693–6703.

38.

Bofill-Cardona

Kudlacek

Yang

. Binding of calmodulin to the D2-dopamine receptor reduces receptor signaling by arresting the G protein activation switch. J Biol Chem. 2000;275:32672–32680.

39.

Eaton

Macias

Youngs

. L-type Ca2+ channel blockers promote Ca2+ accumulation when dopamine receptors are activated in striatal neurons. Brain Res Mol Brain Res. 2004;131:65–72.

40.

Lidow

. Calcium signaling dysfunction in schizophrenia: a unifying approach. Brain Res Brain Res Rev. 2003;43:70–84.

41.

Dogrul

Yeılyurt

Effects on Ca2+ calcium channel blockers on apomorphine, bromocriptine and morphine-induced locomotor activity in mice. Eur J Pharmacol. 1999;364:175–182.

42.

Nurnburger

Jr , Simmons-Alling

Mediation of "calcium antagonist" effects by dopamine receptor blockade. Am J Psychiatry. 1987;144:966–967.

43.

Messerli

McLoughlin

Calcium channel antagonists: what do they offer?

P and T. 1993; 1051–1063.

44.

Snyder

Reynolds

. Calcium-antagonist drugs. Receptor interactions that clarify therapeutic effects. N Engl J Med. 1985;312:995–1002.

45.

Hockerman

Peterson

Johnson

. Molecular determinants of drug binding and action on L-type calcium channels. Annu Rev Pharmacol Toxicol. 1997;37:361–396.

46.

Dubovsky

Buzan

The role of calcium channel blockers in the treatment of psychiatric disorders. CNS Drugs. 1995;4:47–57.

47.

Yamada

Kanba

Ashikari

. Nilvadipine is effective for chronic schizophrenia in a double-blind placebo-controlled study. J Clin Psychopharmacol. 1996;16:437–439.

48.

Lencz

Malhotra

. Targeting the schizophrenia genome: a fast track strategy from GWAS to clinic. Mol Psychiatry. 2015;20:820–826.

49.

Icahn School of Medicine at Mount Sinai; Brain & Behavior Research Foundation. Evaluating isradipine for cognitive enhancement in schizophrenia and schizoaffective disorder. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01658150. Updated August 19, 2017. Accessed April 30 2016.

50.

Levy

Janicak

. Calcium channel antagonists for the treatment of bipolar disorder. Bipolar Disord. 2000;2:108–119.

51.

Kaplan

Calcium entry blockers in the treatment of hypertension. JAMA. 1989;262:817–823.

52.

Nakagami

Yasui-Furukori

Saito

. Effect of verapamil on pharmacokinetics and pharmacodynamics of risperidone: in vivo evidence of involvement of P-glycoprotein in risperidone disposition. Clin Pharmacol Ther. 2005;78:43–51.

53.

Prior

Baker

. Interactions between the cytochrome P450 system and the second-generation antipsychotics. J Psychiatry Neurosci. 2003;28:99–112.

54.

Moons

de Roo

, Claes

, . Relationship between P-glycoprotein and second-generation antipsychotics. Pharmacogenomics. 2011;12:1193–1211.

55.

Zhou

. Drugs behave as substrates, inhibitors and inducers of human cytochromeP450 3A4. Curr Drug Metab. 2008;9:310–322.

56.

Leucht

Engel

Davis

. Equipercentile linking of the Brief Psychiatric Rating Scale and the Clinical Global Impression Scale in a catchment area. Eur Neuropsychopharmacol. 2012;22:501–505.

57.

Leucht

Rothe

Davis

Engel

. Equipercentile linking of the BPRS and the PANSS. Eur Neuropsychopharmacol. 2013;23:956–959.

58.

Grunze

von Wegerer

, Greene

, . Modulation of calcium and potassium currents by lamotrigine. Neuropsychobiology. 1998;38:131–138.

59.

Taylor

Gee

. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res. 1998;29:233–249.