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.
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References
1.
LiebermanJAStroupTSPerkinsDO. The American Psychiatric Publishing textbook of schizophrenia. Arlington, VA: American Psychiatric Publishing, Inc;2006.
2.
RösslerWSalizeHJvanOs J, . Size of burden of schizophrenia and psychotic disorders. Eur Neuropsychopharmacol.2005; 15: 399–409.
3.
SullivanPFKendlerKSNealeMC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry.2003; 60: 1187–1192.
4.
HamshereMLWaltersJTSmithR; 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.
5.
LiaoPSoongTW. CaV1.2 channelopathies: from arrhythmias to autism, bipolar disorder, and immunodeficiency. Pflugers Arch.2010; 460: 353–359.
6.
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature.2014; 511: 421–427.
7.
RipkeSO'DushlaineCChambertK; 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.
8.
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet.2011; 43: 969–976.
9.
JiangHQiaoFLiZ. Evaluating the association between CACNA1C rsl006737 and schizophrenia risk: a meta-analysis. Asia Pac Psychiatry.2015; 7: 260–267.
10.
PorcelliSLeeSJHanC. CACNAIC gene and schizophrenia: a case-control and pharmacogenetic study. Psychiatr Genet.2015; 25: 163–167.
11.
NyegaardMDemontisDFoldagerL. CACNAIC (rsl006737) is associated with schizophrenia. Mol Psychiatry.2010; 15: 119–121.
12.
OrtnerNJStriessnigJ.L-type calcium channels as drug targets in CNS disorders. Channels (Austin).2016; 10: 7–13.
13.
BergerSMBartschD.The role of L-type voltage-gated calcium channels Cavl.2 and Cavl.3 in normal and pathological brain function. Cell Tissue Res.2014; 357: 463–476.
14.
ImbriciPCamerinoDCTricaricoD.Major channels involved in neuropsychiatric disorders and therapeutic perspectives. Front Genet.2013; 4: 76.
15.
KabirZDLeeASRajadhyakshaAM. 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.
BloomDMTourjmanSVNairNP. Verapamil in refractory schizophrenia: a case report. Prog Neuropsychopharmacol Biol Psychiatry.1987; 11: 185–188.
17.
BartkoGHorvathSZadorG. Effects of adjunctive verapamil administration in chronic schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry.1991; 15: 343–349.
18.
PriceWA. Antipsychotic effects of verapamil in schizophrenia. Hillside J Clin Psychiatry.1987; 9: 225–230.
19.
GrebbJASheltonRCTaylorEH. A negative, double-blind, placebo-controlled, clinical trial of verapamil in chronic schizophrenia. Biol Psychiatry.1986; 21: 691–694.
20.
UhrSBJacksonKBergerPA. Effects of verapamil administration on negative symptoms of chronic schizophrenia. Psychiatry Res.1988; 23: 351–352.
21.
StedmanTJWhitefordHAEylesD. Effects of nifedipine on psychosis and tardive dyskinesia in schizophrenic patients. J Clin Psychopharmacol.1991; 11: 43–47.
22.
SchwartzBLFay-McCarthyMKendrickK. Effects of nifedipine, a calcium channel antagonist, on cognitive function in schizophrenic patients with tardive dyskinesia. Clin Neuropharmacol.1997; 20: 364–370.
23.
SuddathRLStrawGMFreedWJ. A clinical trial of nifedipine in schizophrenia and tardive dyskinesia. Pharmacol Biochem Behav.1991; 39: 743–745.
24.
Garza-TreviñoESOverallJEHollisterLE. Verapamil versus lithium in acute mania. Am J Psychiatry.1992; 149: 121–122.
25.
MallingerAGThaseMEHaskettR. 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.
NimmrichVEckertA.Calcium channel blockers and dementia. Br J Pharmacol.2013; 169: 1203–1210.
27.
SilverstonePHBirkettL.Diltiazem as augmentation therapy in patients with treatment-resistant bipolar disorder: a retrospective study. J Psychiatry Neurosci.2000; 25: 276–280.
28.
LiebermanJAStroupTSMcEvoyJP; 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.
StroupTSLiebermanJA. Antipsychotic trials in schizophrenia: the CATIE project. New York, NY: Cambridge University Press; 2010.
30.
vanBuuren S, Groothuis-Oudshoorn CGM. mice: Multivariate imputation by chained equations in R. J Stat Soft.2011; 45: 1–67.
31.
RosenbaumPRRubinDB. The central role of propensity score in observational studies for casual effects. Biometrika.1983; 70: 41–55.
32.
HoDEImaiKKingG. Matchlt: nonparametric preprocessing for parametric casual inference. J Stat Soft.2011; 42: 1–28.
33.
BusnerJTargumSD. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry (Edgmont).2007; 4: 28–37.
34.
KaySRFiszbeinAOplerLA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull.1987; 13: 261–276.
35.
ChobanianAV; 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.
YoshimizuTPanJQMungenastAE. Functional implications of a psychiatric risk variant within CACNAIC in induced human neurons. Mol Psychiatry.2015; 20: 162–169.
37.
BonciAGrillnerPMercuriNB. L-type calcium channels mediate a slow excitatory synaptic transmission in rat midbrain dopaminergic neurons. J Neurosci.1998; 18: 6693–6703.
38.
Bofill-CardonaEKudlacekOYangQ. 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.
EatonMEMaclasWYoungsRM. 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.
LidowMS. Calcium signaling dysfunction in schizophrenia: a unifying approach. Brain Res Brain Res Rev.2003; 43: 70–84.
41.
DoğrulAYeşilyurtO.Effects on Ca2+ calcium channel blockers on apomorphine, bromocriptine and morphine-induced locomotor activity in mice. Eur J Pharmacol.1999; 364: 175–182.
42.
NurnburgerJJr, Simmons-AilingS.Mediation of "calcium antagonist" effects by dopamine receptor blockade. Am J Psychiatry.1987; 144: 966–967.
43.
MesserliFMcLoughlinM.Calcium channel antagonists: what do they offer?P and T.1993; 1051–1063.
44.
SnyderSHReynoldsIJ. Calcium-antagonist drugs. Receptor interactions that clarify therapeutic effects. N Engl J Med.1985; 312: 995–1002.
45.
HockermanGHPetersonBZJohnsonBD. Molecular determinants of drug binding and action on L-type calcium channels. Annu Rev Pharmacol Toxicol.1997; 37: 361–396.
46.
DubovskySLBuzanR.The role of calcium channel blockers in the treatment of psychiatric disorders. CNS Drugs.1995; 4: 47–57.
47.
YamadaKKanbaSAshikariI. Nilvadipine is effective for chronic schizophrenia in a double-blind placebo-controlled study. J Clin Psychopharmacol.1996; 16: 437–439.
48.
LenczTMalhotraAK. 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.
LevyNAJanicakPG. Calcium channel antagonists for the treatment of bipolar disorder. Bipolar Disord.2000; 2: 108–119.
51.
KaplanN.Calcium entry blockers in the treatment of hypertension. JAMA.1989; 262: 817–823.
52.
NakagamiTYasui-FurukoriNSaitoM. 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.
PriorTIBakerGB. Interactions between the cytochromeP450 system and the second-generation antipsychotics. J Psychiatry Neurosci.2003; 28: 99–112.
54.
MoonsTde RooM, ClaesS, . Relationship between P-glycoprotein and second-generation antipsychotics. Pharmacogenomics.2011; 12: 1193–1211.
55.
ZhouSF. Drugs behave as substrates, inhibitors and inducers of human cytochromeP450 3A4. Curr Drug Metab.2008; 9: 310–322.
56.
LeuchtSEngelRRDavisJM. 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.
LeuchtSRothePDavisJMEngelRR. Equip ercentile linking of the BPRS and the PANSS. Eur Neuropsychopharmacol.2013; 23: 956–959.
58.
GrunzeHvon WegererJ, GreeneRW, . Modulation of calcium and potassium currents by lamotrigine. Neuropsychobiology.1998; 38: 131–138.
59.
TaylorCPGeeNSSuTZ. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res.1998; 29: 233–249.
