Cannabis use disorders (CUDs) are highly comorbid in patients with schizophrenia and are associated with poor outcome. Clozapine has been put forward as the first choice antipsychotic in this comorbid group. However, little is known about the mechanisms underlying the assumed superiority of clozapine. We compared the effects of clozapine and risperidone on attentional bias, subjective craving and associated regional brain activity in patients with schizophrenia and CUD. Overall, 36 patients with schizophrenia and 19 healthy controls were included. Patients were randomised to antipsychotic treatment with clozapine or risperidone. At baseline and after 4 weeks of medication use, regional brain responses were measured during a classical Stroop and a cannabis word Stroop using functional magnetic resonance imaging. Clozapine-treated CUD patients showed a larger reduction in craving and in activation of the insula during the cannabis word Stroop, while risperidone-treated patients showed a larger decrease in activation of the right anterior cingulate cortex during the classical Stroop. A significant association was found between decreases in subjective craving and decreases in insula activation during the cannabis word Stroop. These findings strongly suggest that clozapine may be a better treatment choice in patients with schizophrenia and CUD than risperidone.
BassettDBullmoreETMeyer-LindenbergAet al (2009) Cognitive fitness of cost-efficient brain functional networks. Proc Natl Acad Sci U S A106: 11747–11752.
2.
BushGWhalenPJShinLMet al (2006) The counting Stroop: A cognitive interference task. Nat Protoc1: 230–233.
3.
BushGWhalenPJRosenBRet al (1998) The counting Stroop: An interference task specialized for functional neuroimaging – validation study with functional MRI. Hum Brain Mapp6: 270–282.
4.
CarpenterKMSchreiberEChurchSet al (2006) Drug Stroop performance: Relationships with primary substance of use and treatment outcome in a drug-dependent outpatient sample. Addict Behav31: 174–181.
5.
CoxWMFadardiJSPothosEM (2006) The addiction-Stroop test: Theoretical considerations and procedural recommendations. Psychol Bull132: 443–476.
6.
De HaanLWeisfeltMDingemansPet al (2002) Psychometric properties of the subjective well-being under neuroleptics scale and the subjective deficit syndrome scale. Psychopharmacology (Berl)162: 24–28.
7.
de HaanLBooijJLavalayeJet al (2006) Occupancy of dopamine D2 receptors by antipsychotic drugs is related to nicotine addiction in young patients with schizophrenia. Psychopharmacology (Berl)183: 500–505.
8.
DekkerNKoeterMVan Den BrinkWet al (2012) Craving for cannabis in patients with psychotic disorder, their non-affected siblings and healthy controls: Psychometric analysis of the obsessive compulsive drug use scale. Int J Methods Psychiatr Res21: 286–300.
9.
DixonL (1999) Dual diagnosis of substance abuse in schizophrenia: Prevalence and impact on outcomes. Schizophr Res35(Suppl): S93–S100.
10.
ErscheKDBullmoreETCraigKJet al (2010) Influence of compulsivity of drug abuse on dopaminergic modulation of attentional bias in stimulant dependence. Arch Gen Psychiatry67: 632.
11.
FieldMCoxWM (2008) Attentional bias in addictive behaviors: A review of its development, causes, and consequences. Drug Alcohol Depend97: 1–20.
12.
FieldMMunafoMRFrankenIH (2009) A meta-analytic investigation of the relationship between attentional bias and subjective craving in substance abuse. Psychol Bull135: 589–607.
13.
FrankenIH (2003) Drug craving and addiction: integrating psychological and neuropsychopharmacological approaches. Prog Neuropsychopharmacol Biol Psychiatry27: 563–579.
14.
FrankenIHHendriksVMStamCJet al (2004) A role for dopamine in the processing of drug cues in heroin dependent patients. Eur Neuropsychopharmacol14: 503–508.
15.
FrankenIHStamCJHendriksVMet al (2003) Neurophysiological evidence for abnormal cognitive processing of drug cues in heroin dependence. Psychopharmacology (Berl)170: 205–212.
16.
FristonKJHolmesAPolineJBet al (1996) Detecting activations in PET and fMRI: Levels of inference and power. Neuroimage4: 223–235.
17.
GoldsteinRZAlia-KleinNTomasiDet al (2009a) Anterior cingulate cortex hypoactivations to an emotionally salient task in cocaine addiction. Proc Natl Acad Sci U S A106: 9453–9458.
18.
GoldsteinRZTomasiDAlia-KleinNet al (2009b) Dopaminergic response to drug words in cocaine addiction. J Neurosci29: 6001–6006.
19.
GoldsteinRZTomasiDRajaramSet al (2007) Role of the anterior cingulate and medial orbitofrontal cortex in processing drug cues in cocaine addiction. Neuroscience144: 1153–1159.
20.
GreenAINoordsyDLBrunetteMFet al (2008) Substance abuse and schizophrenia: Pharmacotherapeutic intervention. J Subst Abuse Treat34: 61–71.
21.
HeishmanSJEvansRJSingletonEGet al (2009) Reliability and validity of a short form of the Marijuana Craving Questionnaire. Drug Alcohol Depend102: 35–40.
22.
HesterRGaravanH (2009) Neural mechanisms underlying drug-related cue distraction in active cocaine users. Pharmacol Biochem Behav93: 270–277.
23.
JanesACPizzagalliDARichardtSet al (2010) Neural substrates of attentional bias for smoking-related cues: An FMRI study. Neuropsychopharmacology35: 2339–2345.
24.
KaySRFiszbeinAOplerLA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull13: 261–276.
25.
KnowlesEEDavidASReichenbergA (2010) Processing speed deficits in schizophrenia: Reexamining the evidence. Am J Psychiatry167: 828–835.
26.
KuhnSGallinatJ (2011) Common biology of craving across legal and illegal drugs – a quantitative meta-analysis of cue-reactivity brain response. Eur J Neurosci33: 1318–1326.
27.
KurokiTNagaoNNakaharaT (2008) Neuropharmacology of second-generation antipsychotic drugs: A validity of the serotonin-dopamine hypothesis. Prog Brain Res172: 199–212.
28.
LiWvan TolMLiMet al (2014) Regional specificity of sex effects on subcortical volumes across the lifespan in healthy aging. Hum Brain Mapp35: 238–247.
29.
LinszenDHDingemansPMLeniorM E (1994) Cannabis abuse and the course of recent-onset schizophrenic disorders. Arch Gen Psychiatry51: 273–279.
30.
LuijtenMVan MeelCSFrankenIHA (2011a) Diminished error processing in smokers during smoking cue exposure. Pharmacol Biochem Behav97: 514–520.
31.
LuijtenMVeltmanDJHesterRet al (2012) Brain activation associated with attentional bias in smokers is modulated by a dopamine antagonist. Neuropsychopharmacology37: 2772–2779.
32.
LuijtenMVeltmanDJvan den BrinkWet al (2011b) Neurobiological substrate of smoking-related attentional bias. Neuroimage54: 2374–2381.
33.
MachielsenMvan der SluisSde HaanL (2010) Cannabis use in patients with a first psychotic episode and subjects at ultra high risk of psychosis: impact on psychotic- and pre-psychotic symptoms. Aust N Z J Psychiatry44: 721–728.
34.
MachielsenMWde HaanL (2009) Differences in efficacy on substance abuse between risperidone and clozapine supports the importance of differential modulation of dopaminergic neurotransmission. Psychopharmacol Bull42: 40–52.
35.
MarissenMAFrankenIHWatersAJet al (2006) Attentional bias predicts heroin relapse following treatment. Addiction101: 1306–1312.
36.
MinzenbergMJLairdARThelenSet al (2009) Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch Gen Psychiatry66: 811–822.
37.
NaberD (1995) A self-rating to measure subjective effects of neuroleptic drugs, relationships to objective psychopathology, quality of life, compliance and other clinical variables. Int Clin Psychopharmacol10(Suppl3): 133–138.
38.
NestorLMcCabeEJonesJet al (2011) Differences in “bottom-up” and “top-down” neural activity in current and former cigarette smokers: Evidence for neural substrates which may promote nicotine abstinence through increased cognitive control. Neuroimage56: 2258–2275.
39.
NielsenMORostrupEWulffSet al (2012) Improvement of brain reward abnormalities by antipsychotic monotherapy in schizophrenia. Arch Gen Psychiatry69: 1195–1204.
40.
PerlsteinWMCarterCSNollDCet al (2001) Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. Am J Psychiatry158: 1105–1113.
41.
RegierDAFarmerMERaeDSet al (1990) Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA264: 2511–2518.
42.
RobinsLNWingJWittchenHUet al (1988) The Composite International Diagnostic Interview. An epidemiologic instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Arch Gen Psychiatry45: 1069–1077.
43.
RobinsonTEBerridgeKC (1993) The neural basis of drug craving: An incentive-sensitization theory of addiction. Brain Res Brain Res Rev18: 247–291.
44.
Roesch-ElyDScheffelHWeilandSet al (2005) Differential dopaminergic modulation of executive control in healthy subjects. Psychopharmacology (Berl)178: 420–430.
45.
SeemanP (2002) Atypical antipsychotics: Mechanism of action. Can J Psychiatry47: 27–38.
46.
StroopJR (1935) Studies of interference in serial verbal reactions. J Exp Psychol18: 643–6620.
47.
TauscherJHussainTAgidOet al (2004) Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: Differentiation from other atypical antipsychotics. Am J Psychiatry161: 1620–1625.
48.
Tzourio-MazoyerNLandeauBPapathanassiouDet al (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage15: 273–289.
49.
VerheulRvan den BrinkWGeerlingsP (1999) A three-pathway psychobiological model of craving for alcohol. Alcohol Alcohol34: 197–222.
50.
VolkowNDFowlerJSWangGJet al (2007) Dopamine in drug abuse and addiction: Results of imaging studies and treatment implications. Arch Neurol64: 1575–1579.
51.
Vollstadt-KleinSLoeberSRichterAet al (2012) Validating incentive salience with functional magnetic resonance imaging: Association between mesolimbic cue reactivity and attentional bias in alcohol-dependent patients. Addict Biol17: 807–816.
52.
VorugantiLNAwadAG (2006) Subjective and behavioural consequences of striatal dopamine depletion in schizophrenia – findings from an in vivo SPECT study. Schizophr Res88: 179–186.
53.
WatersAJShiffmanSBradleyBPet al (2003) Attentional shifts to smoking cues in smokers. Addiction98: 1409–1417.
54.
WilkinsonDHalliganP (2004) The relevance of behavioural measures for functional-imaging studies of cognition. Nat Rev Neurosci5: 67–73.
55.
WobrockTFalkaiPSchneider-AxmannTet al (2013) Comorbid substance abuse in first-episode schizophrenia: Effects on cognition and psychopathology in the EUFEST study. Schizophr Res147: 132–139.
56.
WorsleyKJMarrettSNeelinPet al (1996) A unified statistical approach for determining significant signals in images of cerebral activation. Hum Brain Mapp4: 58–73.
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