Abstract
Substance use disorder is the most common psychiatric comorbidity in schizophrenic patients, with prevalence rates of up to 65%. Besides the legal substances tobacco and alcohol, cannabis seems to be the most illicit drug abused in schizophrenia patients and has been discussed as an important risk factor for developing schizophrenia. At least substance abuse may contribute to an earlier onset of schizophrenia as seen in many first-episode studies. Common hypothetic models for the increased comorbidity include the concept of increased vulnerability to each individual disorder, the model of a secondary substance use or psychotic disorder, and the bidirectional model. There is no common sense regarding a different neurobiological background for schizophrenia patients with and without substance abuse. Previous substance abuse (primarily cannabis) seems not to lead to pronounced structural brain abnormalities in schizophrenia, but may cause functional changes on cortical inhibition processes and synaptic transmission involving mainly the GABAegic, glutamatergic and dopaminergic system. The key issue in providing treatment for this population is developing a dual disorder approach that integrates treatment of substance abuse and schizophrenia. Many programmes are now providing this integration through interdisciplinary teams with expertise in the treatment of schizophrenia and substance abuse. This form of treatment features assertive outreach, case management, family interventions, housing, rehabilitation and pharmacotherapy. It also includes a stagewise motivational approach for patients who do not recognize the need for treatment of substance use disorders and behavioural interventions for those who are trying to attain or maintain abstinence. Nevertheless, that the evaluation of combined treatment programs with motivational elements, psychoeducation and cognitive-behavioural approaches shows an effect in reducing substance abuse and in decreasing frequency and severity of psychotic decompensations, there is only a slight advantage over routine care. Pharmacotherapy of patients with the dual diagnosis of a schizophrenia and comorbid substance use disorder is a highly challenging topic because this subgroup of patients shows a high relapse rate, low treatment adherence and high rate of side effects. Recommendations for antipsychotic pharmacotherapy in schizophrenia are mainly based on studies that excluded patients with this dual diagnosis. The preferred pharmacological strategy depends on the target symptoms: improvement of schizophrenic psychopathology, reduction of craving and substance use, treatment of concomitant symptoms like depressive mood or management of side effects. Data, mainly based on open studies or case series, suggest superior efficacy for second generation antipsychotics (SGAs) over conventional antipsychotics (FGAs) with regard to improvement of the above mentioned target symptoms. Antidepressants and anti-craving agents (naltrexone) given adjunctive to antipsychotic maintenance therapy showed efficacy in reducing substance use and craving. In conclusion, there is an increasing need to proceed researching the pathophysiological background of this comorbidity to develop new treatment approaches. The insight into the pathomechanisms of the endocannabinoid system may help to find innovative treatment strategies in schizophrenia without substance abuse.
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Abbreviations
- 2-AG:
-
2-arachidonoylglycerol
- ACC:
-
Anterior cingulated gyrus
- ACT:
-
Assertive community treatment
- AEA:
-
Anandamide
- BDNF:
-
Brain derived neurotrophic factor
- CB1:
-
Cannabinoid receptor 1
- CBD:
-
Cannabidiol
- CBT:
-
Cognitive behavioural therapy
- CM:
-
Case management
- CNR1:
-
Cannabinoid receptor 1 gene
- COMT:
-
Catechol-O-methyltransferase
- CSF:
-
Cerebro-spinal fluid
- D2-receptor:
-
Dopamine-2-receptor
- delta-9-THC:
-
Delta-9-tetrahydrocannabinol
- DRT:
-
Dual recovery therapy
- eCS:
-
Endogenous cannabinoid system
- EPS:
-
Extra-pyramidal symptoms
- ERP:
-
Event-related potentials
- FAAH:
-
Fatty acid amide hydrolase
- FGA:
-
First-generation antipsychotics
- GABA:
-
Gamma amino butyric acid
- ICF:
-
Intracranial facilitation
- MAO:
-
Monoaminooxidase
- MET:
-
Modified motivational enhancement therapy
- MI:
-
Motivational interviewing
- MMN:
-
Mismatch negativity
- MRI:
-
Magnetic resonance imaging
- NMDA:
-
N-methyl D-aspartate
- NRG1:
-
Neuregulin 1 gene
- PANSS:
-
Positive and negative symptome scale
- PFC:
-
Prefrontal cortex
- RCT:
-
Randomised controlled trial
- ROI:
-
Region of interest
- SAMM:
-
Substance abuse management module
- SGA:
-
Second-generation antipsychotics
- SICI:
-
Short interval cortical inhibition
- Smri:
-
Structural magnetic resonance imaging
- ST:
-
Skills training
- STG:
-
Superior temporal gyrus
- SUD:
-
Substance use disorder
- TMS:
-
Transcranial magnetic stimulation
References
Wobrock T, Pajonk FG, D’Amelio R, Falkai P (2005) Schizophrenia and addiction. PsychoNeuro 31:433–440
Cantor-Graae E, Nordstrom LG, McNeil TF (2001) Substance abuse in schizophrenia: a review of the literature and a study of correlates in Sweden. Schizophr Res 48:69–82
Mueser KT, Yarnold PR, Levinson DF et al (1990) Prevalence of substance abuse in schizophrenia: demographic and clinical correlates. Schizophr Bull 16:31–56
Regier DA, Farmer ME, Rae DS et al (1990) Comorbidity of mental disorders with alcohol and other drug abuse. Results from the epidemiologic catchment area (ECA) Study. JAMA 264:2511–2518
Cohen LJ, Test MA, Brown RL (1990) Suicide and schizophrenia: data from a prospective community treatment study. Am J Psychiatry 147:602–607
Haywood TW, Kravitz HM, Grossman LS et al (1995) Predicting the “revolving door” phenomenon among patients with schizophrenic, schizoaffective, and affective disorders. Am J Psychiatry 152:856–861
Kovasznay B, Fleischer J, Tanenberg-Karant M et al (1997) Substance use disorder and the early course of illness in schizophrenia and affective psychosis. Schizophr Bull 23(2):195–201
Linszen DH, Dingemans PM, Lenior ME (1994) Cannabis abuse and the course of recent-onset schizophrenic disorders. Arch Gen Psychiatry 51:273–279
Rasanen P, Tiihonen J, Isohanni M et al (1998) Schizophrenia, alcohol abuse, and violent behavior: a 26-year followup study of an unselected birth cohort. Schizophr Bull 24:437–441
Seibyl JP, Satel SL, Anthony D et al (1993) Effects of cocaine on hospital course in schizophrenia. J Nerv Ment Dis 181:31–37
Soyka M, Albus M, Kathmann N et al (1993) Prevalence of alcohol and drug abuse in schizophrenic inpatients. Eur Arch Psychiatry Clin Neurosci 242:362–372
Swofford CD, Kasckow JW, Scheller-Gilkey G, Inderbitzin LB (1996) Substance use: a powerful predictor of relapse in schizophrenia. Schizophr Res 20:145–151
Mueser KT, Drake RE, Wallach MA (1998) Dual diagnosis: a review of etiological theories. Addict Behav 23:717–734
Falkai P, Wobrock T, Lieberman J et al (2005) World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, Part 1: acute treatment of schizophrenia. World J Biol Psychiatry 6:132–191
Soyka M, Kranzler HR, Berglund M et al (2008) World federation of societies of biological psychiatry (WFSBP) guidelines for biological treatment of substance use and related disorders, part 1: alcoholism. World J Biol Psychiatry 9:6–23
Caspari D (1999) Cannabis and schizophrenia: results of a follow-up study. Eur Arch Psychiatry Clin Neurosci 249:45–49
Soyka M, Albus M, Immler B, Kathmann N, Hippius H (2001) Psychopathology in dual diagnosis and non-addicted schizophrenics – are there differences? Eur Arch Psychiatry Clin Neurosci 251:232–238
Bühler B, Hambrecht M, Löffler W, An der Heiden W, Häfner H (2002) Precipitation and determination of the onset and course of schizophrenia by substance abuse – a retrospective and prospective study of 232 population-based first illness episodes. Schizophr Res 54:243–251
Peralta V, Cuesta MJ (1992) Influence of cannabis abuse on schizophrenic psychopathology. Acta Psychiatr Scand 85:127–130
Bersani G, Orlandi V, Kotzalidis GD, Pancheri P (2002) Cannabis and schizophrenia: impact on onset, course, psychopathology and outcomes. Eur Arch Psychiatry Clin Neurosci 252:86–92
Dixon L, Haas G, Weiden PJ, Sweeney J, Frances AJ (1991) Drug abuse in schizophrenic patients: clinical correlates and reasons for use. Am J Psychiatry 14:224–230
Wobrock T, Sittinger H, Behrendt B, D’Amelio R, Falkai P, Caspari D (2007) Comorbid substance abuse and neurocognitive function in recent-onset schizophrenia. Eur Arch Psychiatry Clin Neurosci 257:203–210
Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE (2002) Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ 325:1212–1213
Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, van Os J (2006) Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ 330:11–16
van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H (2002) Cannabis use and psychosis: a longitudinalpopulation-based study. Am J Epidemiol 156:319–327
Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G (2002) Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ 325:1199–1203
Andreasson S, Allebeck P, Engstrom A, Rydberg U (1989) Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet 2:1483–1486
Andreasson S, Allebeck P, Rydberg U (1989) Schizophrenia in users and nonusers of cannabis. A longitudinal study in Stockholm County. Acta Psychiatr Scand 79:505–510
Wobrock T, Sittinger H, Behrendt B, D’Amelio R, Falkai P (2009) Comorbid substance abuse and brain morphology in recent-onset psychosis. Eur Arch Psychiatry Clin Neurosci 259(1):28–36
Wobrock T, Hasan A, Malchow B, Wolff-Menzler C, Guse B, Lang N, Schneider-Axmann T, Ecker UK, Falkai P (2010) Increased cortical inhibition deficits in first-episode schizophrenia with comorbid cannabis abuse. Psychopharmacology (Berl) 208(3):353–363
Bilder RM, Goldman RS, Robinson D, Reiter G, Bell L, Bates JA, Pappadopulos E, Willson DF, Alvir JMJ, Woerner MG, Geisler S, Kane JM, Lieberman JA (2000) Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. Am J Psychiatry 157:549–559
Falkai P, Tepest R, Schulze TG et al (2004) Etiopathogenetic mechanisms in long-term course of schizophrenia. Pharmacopsychiatry 37(suppl 2):s136–s140
Heinrichs RW, Zakzanis KK (1998) Neurocognitive deficit in schizophrenia:a quantitative review of the evidence. Neuropsychology 12:426–445
Torrey EF (2002) Studies of individuals with schizophrenia never treated with antipsychotic medications: a review. Schizophr Res 58:101–115
Jensen J, Nilsson LL, Levander S (2004) Neurocognitive and psychopathological correlates of self-monitoring ability in schizophrenia. Eur Arch Psychiatry Clin Neurosci 254:312–317
Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153:321–330
O’Malley S, Adamse M, Heaton RK, Gawin FH (1992) Neuropsychological impairment in chronic cocaine abusers. Am J Drug Alcohol Abuse 18:131–144
Beatty WW, Katzung VM, Moreland VJ, Nixon SJ (1995) Neuropsychological performance of recently abstinent alcoholics and cocaine abusers. Drug Alcohol Depend 37:247–253
Pope HG, Gruber AJ, Yurgelun-Todd D (1995) The residual neuropsychological effects of cannabis: the current status of research. Drug Alcohol Depend 38:25–34
Pencer A, Addington J (2003) Substance use and cognition in early psychosis. J Psychiatry Neurosci 28:48–54
Sevy S, Kay SR, Opler LA, van Praag HM (1990) Significance of cocaine history in schizophrenia. J Nerv Ment Dis 178:642–648
Allen DN, Goldstein G, Aldarondo F (1999) Neurocognitive dysfunction in patients diagnosed with schizophrenia and alcoholism. Neuropsychology 13:62–68
Serper MR, Alpert M, Richardson WA, Dickson S, Allen MH, Werner A (1995) Clinical effects of recent cocaine use on patients with acute schizophrenia. Am J Psychiatry 152:1464–1469
Bowie CR, Serper MR, Raggio S, Harvey PD (2005) Neurocognition, symptomatology, and functional skills in older alcohol-abusing schizophrenia patients. Schizophr Bull 31:175–182
Cleghorn JM, Kaplan RD, Szechtman B, Szechtman H, Brown GM, Franco S (1991) Substance abuse and schizophrenia: effects on symptoms but not on neurocognitive function. J Clin Psychiatry 52:26–30
Nixon SJ, Hallford HG, Tivis RD (1996) Neurocognitive function in alcoholic, schizophrenic, and dually diagnosed patients. Psychiatry Res 64:35–45
Addington J, Addington D (1997) Substance abuse and cognitive functioning in schizophrenia. J Psychiatry Neurosci 22:99–104
Cooper L, Liberman D, Tucker D, Nuechterlein KH, Tsuang J, Barnett HL (1999) Neurocognitive deficits in the dually diagnosed with schizophrenia and cocaine abuse. Psychiatr Rehab Skills 3:231–245
Liraud F, Verdoux H (2002) Effect of comorbid substance use on neuropsychological performance in subjects with psychosis or mood disorders. Encephale 8:160–168
Joyal CC, Halle P, Lapierre D, Hodgins S (2003) Drug abuse and/or dependence and better neuropsychological performance in patients with schizophrenia. Schizophr Res 63:297–299
Herman M (2004) Neurocognitive functioning and quality of life among dually diagnosed and non-substance abusing schizophrenia inpatients. Int J Ment Health Nurs 13:282–291
Potvin S, Briand C, Prouteau A, Bouchard RH, Lipp O, Lalonde P, Nicole L, Lesage A, Stip E (2005) CANTAB explicit memory is less mpaired in addicted schizophrenics. Brain Cogn 59(1):38–42
Eckhardt MJ, Stapleton JM, Rawlings RR, Davis EZ, Grondin DM (1995) Neuropsychological functioning in detoxified alcoholics between 18 and 35 years of age. Am J Pschiatry 153:53–59
Andreasen NC (2000) Schizophrenia: the fundamental questions. Brain Res Rev 31:106–112
Shenton ME, Dickey CC, Frumin M, McCarley RW (2001) A review of MRI findings in schizophrenia. Schizophr Res 49:1–52
Wright IC, Rabe-Hesketh S, Woodruff PWR, David AS, Murray RM, Bullmore ET (2000) Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 157:16–25
Chua SE, Lam IW, Tai KS et al (2003) Brain morphological abnormality in schizophrenia is independent of country of origin. Acta Psychiatr Scand 108:269–275
Nelson MD, Saykin AJ, Flashman LA, Riordan HJ (1998) Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: a meta-analytic study. Arch Gen Psychiatry 55:433–440
Shenton ME, Kikinis R, Jolesz FA et al (1992) Abnormalities of the left temporal lobe and thought disorder in schizophrenia: a quantitative magnetic resonance imaging study. N Engl J Med 327:604–612
Gur RE, Turetsky BI, Cowell PE et al (2000) Temporolimbic volume reductions in schizophrenia. Arch Gen Psychiatry 57:769–775
Barta PE, Pearlson GD, Powers RE, Richards SS, Tune LE (1990) Auditory hallucinations and smaller superior temporal gyral volume in schizophrenia. Am J Psychiatry 147:1457–1462
Torrey EF (2002) Studies of individuals with schizophrenia never treated with antipsychotic medications: a review. Schizophr Res 58:101–115
Ettinger U, Chitnis XA, Kumari V, Fannon DG, Sumich AL, O’Ceallaigh S, Doku VC, Sharma T (2001) Magnetic resonance imaging of the thalamus in first-episode psychosis. Am J Psychiatry 158:116–118
Gilbert AR, Rosenberg DR, Harenski K, Spencer S, Sweeney JA, Keshavan MS (2001) Thalamic volumes in patients with first-episode schizophrenia. Am J Psychiatry 158:618–624
Gur RE, Cowell P, Turetsky BI, Gallacher F, Cannon T, Bilker W, Gur RC (1998) A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry 55:145–152
Joyal CC, Laakso MP, Tiihonen J et al (2002) A volumetric MRI study of the entorhinal cortex in first episode neuroleptic-naive schizophrenia. Biol Psychiatry 51:1005–1007
Szeszko PR, Goldberg E, Gunduz-Bruce H et al (2003) Smaller anterior hippocampal formation volume in antipsychotic-naive patients with first-episode schizophrenia. Am J Psychiatry 160:2190–2197
Quickfall J, Crockford D (2006) Brain neuroimaging in cannabis use: a review. J Neuropsychiatry Clin Neurosci 18:318–332
Block RI, O’Leary DS, Ehrhardt JC, Augustinack JC, Ghoneim MM, Arndt S, Hall JA (2000) Effects of frequent marijuana use on brain tissue volumes and composition. Neuroreport 11:491–596
Tzilos GK, Cintron CB, Wood JB, Simpson NS, Young AD, Pope HG Jr, Yurgelun-Todd DA (2005) Lack of hippocampal volume change in long-term heavy cannabis users. Am J Addict 14:64–72
Matochik JA, Eldreth DA, Cadet JL, Bolla KI (2005) Altered brain tissue composition in heavy marijuana users. Drug Alcohol Depend 77:23–30
Schlaepfer TE, Lancaster E, Heidbreder R, Strain EC, Kosel M, Fisch HU, Pearlson GD (2006) Decreased frontal white-matter volume in chronic substance abuse. Int J Neuropsychopharmacol 9:147–153
Wilson W, Mathew R, Turkington T, Hawk T, Coleman RE, Provenzale J (2000) Brain morphological changes and early marijuana use: a magnetic resonance and positron emission tomography study. J Addict Dis 19:1–22
Cahn W, Hulshoff Pol HE, Caspers E, van Haren NE, Schnack HG, Kahn RS (2004) Cannabis and brain morphology in recent-onset schizophrenia. Schizophr Res 67:305–307
Rais M, Cahn W, Van Haren N, Schnack H, Caspers E, Hulshoff Pol H, Kahn R (2008) Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients. Am J Psychiatry 165:490–496
Szeszko PR, Robinson D, Sevy S, Kumra S, Rupp CI, Betensky JD, Lencz T, Ashtari M, Kane JM, Malhotra AK, Gunduz-Bruce H, Napolitano B, Bilder RM (2007) Anterior cingulate grey-matter deficits and cannabis use in first-episode schizophrenia. Br J Psychiatry 190:230–236
Wobrock T, Gruber O, Schneider-Axmann T, Wölwer W, Gaebel W, Riesbeck M, Maier W, Klosterkötter J, Schneider F, Buchkremer G, Möller HJ, Schmitt A, Bender S, Schlösser R, Falkai P (2009) Internal capsule size associated with outcome in first-episode schizophrenia. Eur Arch Psychiatry Clin Neurosci 259:278–283
Adler LE, Pachtman E, Frank RD, Pecevich M, Waldo MC, Freedman R (1982) Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry 17:639–654
Solowij N, Michie PT (2007) Cannabis and cognitive dysfunction: Parallels with endophenotypes of schizophrenia? J Psychiatry Neurosci 32(1):30–52
Coburn KL, Shillcutt SD, Tucker KA, Estes KM, Brin FB, Merai P, Moore NC (1998) P300 delay and attenuation in schizophrenia: reversal by neuroleptic medication. Biol Psychiatry 44:466–474
Frommann I, Brinkmeyer J, Ruhrmann S, Hack E, Brockhaus-Dumke A, Bechdolf A, Wölwer W, Klosterkötter J, Maier W, Wagner M (2008) Auditory P300 in individuals clinically at risk for psychosis. Int J Psychophysiol 70:192–205
Ozgürdal S, Gudlowski Y, Witthaus H, Kawohl W, Uhl I, Hauser M, Gorynia I, Gallinat J, Heinze M, Heinz A, Juckel G (2008) Reduction of auditory event-related P300 amplitude in subjects with at-risk mental state for schizophrenia. Schizophr Res 105:272–278
Roser P, Juckel G, Rentzsch J, Nadulski T, Gallinat J, Stadelmann AM (2008) Effects of acute oral Delta9-tetrahydrocannabinol and standardized cannabis extract on the auditory P300 event-related potential in healthy volunteers. Eur Neuropsychopharmacol 18:569–577
Umbricht D, Krljes S (2005) Mismatch negativity in schizophrenia: a meta-analysis. Schizophr Res 76:1–23
Roser P, Della B, Norra C, Uhl I, Brüne M, Juckel G (2010 Feb 2) Auditory mismatch negativity deficits in long-term heavy cannabis users. Eur Arch Psychiatry Clin Neurosci 260(6):491–498
Kujirai T, Caramis MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Arsden CD (1993) Corticospinal inhibition in human motor cortex. J Physiol 471:501–519
Ziemann U (2004) TMS and drugs. Clin Neurophysiol 115:1717–1729
Daskalakis ZJ, Christensen BK, Chen R, Fitzgerald PB, Zipursky RB, Kapur S (2002) Evidence for impaired cortical inhibition in schizophrenia using transcranial magnetic stimulation. Arch Gen Psychiatry 59:347–354
Fitzgerald PB, Brown TL, Daskalakis ZJ deCastella A, Kulkarni J (2002) A study of transcallosal inhibition in schizophrenia using transcranial magnetic stimulation. Schizophr Res 56:199–209
Pascual-Leone A, Manoach DS, Birnbaum R, Goff DC (2002) Motor cortical excitability in schizophrenia. Biol Psychiatry 52:24–31
Wobrock T, Schneider M, Kadovic D, Schneider-Axmann T, Ecker UK, Retz W, Rösler M, Falkai P (2008) Reduced cortical inhibition in first-episode schizophrenia. Schizophr Res 105:252–261
Wobrock T, Schneider-Axmann T, Retz W, Rösler M, Kadovic D, Falkai P, Schneider M (2009b) Motor circuit abnormalities in first-episode schizophrenia assessed with transcranial magnetic stimulation. Pharmacopsychiatry 42(5):194–201
Hashimoto T, Bazmi HH, Mirnics K, Wu Q, Sampson AR, Lewis DA (2008) Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia. Am J Psychiatry 165:479–489
D’Souza DC, Sewell RA, Ranganathan M (2009) Cannabis and psychosis/schizophrenia: human studies. Eur Arch Psychiatry Clin Neurosci 259(7):413–431
Meyer-Lindenberg A, Nichols T, Callicott JH, Ding J, Kolachana B, Buckholtz J, Mattay VS, Egan M, Weinberger DR (2006) Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry 11:867–877
Henquet C, Rosa A, Krabbendam L, Papiol S, Fananás L, Drukker M, Ramaekers JG, van Os J (2006) An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition. Neuropsychopharmacol 31(12):2748–2757
Leweke FM, Koethe D (2008) Cannabis and psychiatric disorders: it is not only addiction. Addict Biol 13:264–275
Zammit S, Spurlock G, Williams H, Norton N, Williams N, O’Donovan MC, Owen MJ (2007) Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use. Br J Psychiatry 191:402–407
Boucher AA, Arnold JC, Duffy L, Schofield PR, Micheau J, Karl T (2007) Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Delta9-tetrahydrocannabinol. Psychopharmacology (Berl) 192(3):325–336
Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682
Piomelli D, Giuffrida A, Calignano A, Rodríguez de Fonseca F (2000) The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol Sci 21(6):218–224
Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D (1999) Elevated endogenous cannabinoids in schizophrenia. Neuroreport 1999(10):1665–1665
Giuffrida A, Leweke FM, Gerth CW, Schreiber D, Koethe D, Faulhaber J, Klosterkötter J, Piomelli D (2004) Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacol 29:2108–2114
Leweke FM, Schreiber D, Kranaster L, Gross S, Hoyer C, Klosterkötter J, Hellmich M, Giuffrida A, Piomelli D, Koethe D (2007) Endocannabinoids in CSF of patients suffering initial prodromal states of psychosis. Program No 118.3.2007. Neuroscience Meeting Planner, San Diego, CA, Society for Neuroscience.
Leweke FM, Giuffrida A, Koethe D, Schreiber D, Nolden BM, Neatby MA, Schneider M, Gerth CW, Klosterkötter J, Piomelli D (2007) Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: impact of cannabis use. Schizophr Res 94:29–36
Pacher P, Bátkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58(3):389–462
Drake RE (2007) Management of substance use disorder in schizophrenia patients: current guidelines. CNS Spectr 12(10 (Suppl 17)):27–32
Ziedonis DM, Smelson D, Rosenthal RN et al (2005) Improving the care of individuals with schizophrenia and substance use disorders: consensus recommendations. J Psychiatr Pract 11(5):315–339
Drake RE, Mueser KT (2000) Psychosocial approaches to dual diagnosis. Schizophr Bull 26:105–118
Dickey B, Azeni H (1996) Persons with dual diagnosis of substance abuse and major mental illness: their excess costs of psychiatric care. Am J Pub Health 86:973–977
Owen C, Rutherford V, Jones M et al (1997) Noncompliance in psychiatric aftercare. Com Ment Health J 33:25–34
Carey KB (1996) Substance use reduction in the context of outpatient psychiatric treatment: a collaborative, motivational, harm reduction approach. Com Ment Health J 32:291–306
Gouzoulis-Mayfrank E (2004) Dual diagnosis of psychosis and addiction. From principles to practice. Nervenarzt 75(7):642–650
McHugo GJ, Drake RE, Burton HL, Ackerson TH (1995) A scale for assessing the stage of substance abuse treatment in persons with severe mental illness. J Nerv Ment Dis 183:762–767
Roth RM, Brunette MF, Green AI (2005) Treatment of substance use disorders in schizophrenia: a unifying neurobiological mechanism? Curr Psychiatry Rep 7(4):283–291
Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–483
Fleischhacker WW (2002) Second generation antipsychotics. Psychopharmacology 162:90–91
Möller HJ (2000) Definition, psychopharmacological basis and clinical evaluation of novel/atypical neuroleptics: methodological issues and clinical consequences. World J Biol Psychiatry 1:75–91
Lieberman JA, Stroup TS, McEvoy JP et al (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223
Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW (2006) Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 63(10):1079–1087
Soyka M (1996) Dual diagnosis in patients with schizophrenia. Issues in pharmacological treatment. CNS Drugs 5:414–425
Wilkins JN (1997) Pharmacotherapy of schizophrenia patients with comorbid substance abuse. Schizophr Bull 23:215–228
Bowers MB Jr, Mazure CM, Nelson JC, Jatlow PI (1990) Psychotogenic drug use and neuroleptic response. Schizophr Bull 16(1):81–85
Scheller-Gilkey G, Woolwine BJ, Cooper I et al (2003) Relationship of clinical symptoms and substance use in schizophrenia patients on conventional versus atypical antipsychotics. Am J Drug Alc Abuse 29:553–566
Stuyt EB, Sajbel TA, Allen MH (2006) Differing effects of antipsychotic medications on substance abuse treatment patients with co-occuring psychotic and substance abuse disorders. Am J Addict 15:166–173
Petrakis IL, Leslie D, Finney JW, Rosenheck R (2006) Atypical antipsychotic medication and substance use-related outcomes in the treatment of schizophrenia. Am J Addict 15(1):44–49
Swanson J, Van Dorn RA, Swartz MS (2007) Effectiveness of atypical antipsychotics for substance use in schizophrenia patients. Schizophr Res 94(1–3):114–118
Brunette MF, Drake RE, Xie H et al (2006) Clozapine use and relapses of substance use disorder among patients with co-occuring schizophrenia and substance use disorders. Schizophr Bull 32(4):637–643
Buckley P, Thompson PA, Way L, Meltzer HY (1994) Substance use among patients with treatment-resistant schizophrenia: characteristics and implication for clozapine therapy. Am J Psychiatry 151:385–389
Buckley P, Thompson PA, Way L, Meltzer HY (1994) Substance use and clozapine treatment. J Clin Psychiatry 55(Suppl. B):114–116
Drake RE, Xie H, McHugo GJ, Green AI (2000) The effects of clozapine on alcohol and drug use disorders among patients with schizophrenia. Schizophr Bull 26(2):441–449
Kelly DL, Gale EA, Conley RR (2003) Clozapine treatment in patients with prior substance abuse. Can J Psychiatry 48:111–114
Lee ML, Dickson RA, Campbell M et al (1998) Clozapine and substance abuse in patients with schizophrenia (letter). Can J Psychiatry 43:855–856
Marcus P, Snyder R (1995) Reduction of comorbid substance abuse with clozapine (letter). Am J Psychiatry 152:959
Zimmet S, Strous RD, Burgess E et al (2000) Effects of clozapine on substance use in patients with schizophrenia and schizoaffective disorder. J Clin Psychopharmacol 20:94–98
Berk M, Brook S, Trandafir AI (1999) A comparison of olanzapine with haloperidol in cannabis-induced psychotic disorder: a double-blind randomized controlled trial. Int Clin Psychopharmacol 14(3):177–180
Sayers SL, Campbell EC, Kondrich J et al (2005) Cocaine abuse in schizophrenic patients treated with olanzapine versus haloperidol. J Nerv Ment Dis 193(6):379–386
Smelson DA, Ziedonis D, Williams J et al (2006) The efficacy of olanzapine for decreasing cue-elicited craving in individuals with schizophrenia and cocaine dependence: a preliminary report. J Clin Psychopharmacol 26(1):9–12
Akerele E, Levin FR (2007) Comparison of olanzapine to risperidone in substance-abusing individuals with schizophrenia. Am J Addict 16:260–268
Littrell KH, Petty RG, Hilligoss NM et al (2001) Olanzapine treatment for patients with schizophrenia and substance abuse. J Subst Abuse Treat 21:217–221
Noordsy DL, O’Keefe C (1999) Effectiveness of combining atypical antipsychotics and psychosocial rehabilitation in a community mental health center setting. J Clin Psychiatry 60(Suppl. 19):47–51
Noordsy DL, O’Keefe C, Mueser KT, Xie H (2001) Six-month outcomes for patients who switched to olanzapine treatment. Psychiatr Serv 52:501–507
Gerra G, Di Petta G, D’Amore A et al (2007) Combination of olanzapine with opioid-agonists in the treatment of heroin-addicted patients affected by comorbid schizophrenia spectrum disorders. Clin Neuropharmacol 30:127–135
Tsuang J, Marder SR, Han A, Hsieh W (2002) Olanzapine treatment for patients with schizophrenia and cocaine abuse (letter). J Clin Psychiatry 63:1180–1181
Green AI, Tohen MF, Hamer RM et al (2004) First episode schizophrenia-related psychosis and substance use disorders: acute response to olanzapine and haloperidol. Schizophr Res 66(2–3):125–135
Conley RR, Kelly DL, Gale EA (1998) Olanzapine response in treatment-refractory schizophrenic patients with a history of substance abuse. Schizophr Res 33:95–101
Brown ES, Nejtek VA, Perantie DC et al (2003) Cocaine and amphetamine use in patients wih psychiatric illness. A randomized trial of typical antipsychotic continuation or discontinuation. J Clin Psychopharmacol 23:384–388
Potvin S, Stip E, Lipp O, Elie R et al (2006) Quetiapine in patients with comorbid schizophrenia-spectrum and substance use disorders: an open-label trial. Curr Med Res Opin 22(7):1277–1285
Potvin S, Stip E, Roy JY (2004) The effect of quetiapine on cannabis use in 8 psychosis patients with drug dependency. Can J Psychiatry 49(10):711
Weisman RL (2003) Quetiapine in the successful treatment of schizophrenia with comorbid alcohol and drug dependence: a case report. Int J Psychiatry Med 33:85–89
Berk M, Brook S, Nur F (2000) Risperidone compared to haloperidol in cannabis-induced psychotic disorder: a double-blind randomized controlled trial. Int J Psych Clin Pract 4:139–142
Smelson DA, Losonczy MF, Davis CW et al (2002) Risperidone decreases craving and relapses in individuals with schizophrenia and cocain dependence. Can J Psychiatry 47:671–675
Albanese MJ, Khantzian EJ, Murphy SL, Green AI (1994) Decreased substance use in chronically psychotic patients treated with clozapine (letter). Am J Psychiatry 151:780–781
Gupta N, Basu D (2001) Does risperidon reduce concomitant substance abuse in cases of schizophrenia? Can J Psychiatry 46:862–863
Tsuang J, Eckman T, Marder SR, Tucker D (2002) Can risperidone reduce cocaine use in substance abusing schizophrenic patients? (letter). J Clin Psychiatry 22(6):629–630
Green AI, Burgess ES, Dawson R et al (2003) Alcohol and cannabis use in schizophrenia: effects of clozapine vs. risperidone. Schizophr Res 60(1):81–85
Kim JH, Kim D, Marder SR (2008) Time to rehospitalization of clozapine versus risperidone in the naturalistic treatment of comorbid alcohol use disorder and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 32(4):984–988
Beresford TP, Clapp L, Martin B, Wiberg JL (2005) Aripiprazole in schizophrenia with cocaine dependence. A pilot study. J Clin Psychopharmacol 25(4):363–366
Desseilles M, Mathot F, Desseilles M (2008) Aripiprazole diminishes cannabis use in schizophrenia. J Neuropsychiatry Clin Neurosci 20(1):117–118
Dervaux A, Cazali J (2007) Clozapine and amisulpride in refractory schizophrenia and alcohol dependence. J Clin Psychopharmacol 27(5):514–516
Swartz MS, Wagner HR, Swanson JW et al (2008) CATIE Investigators. The effectiveness of antipsychotic medications in patients who use or avoid illicit substances: results from the CATIE study. Schizophr Res 100(1-3):39–52
Soni SD, Brownlee M (1991) Alcohol abuse in chronic schizophrenics: implications for management in the community. Acta Psychiatr Scand 84:272–276
Levin RF, Evans SM, Coomaraswammy S et al (1998) Flupentixol treatment for cocaine abusers with schizophrenia: a pilot study. Am J Drug Alcohol Abuse 24:343–360
Schilkrut R, Cabrera J, Morales E, Herrera L (1998) Neuroleptics in the treatment of drug dependence in schizophrenics. A study with flupenthixol decanoate. Psychopharmacology 96(Suppl.):342, (Abstract Nr. 33.01.50)
Soyka M, Sand P (1995) Successful treatment with flupenthixol decanoate of a patient with both schizophrenia and alcoholism. Pharmacopsychiatry 28:64–65
Soyka M, Aichmüller C, von Bardeleben U et al (2003) Flupenthixol in relapse prevention in schizophrenics with comorbid alcoholism: results from an open clinical study. Eur Addict Res 9:65–72
Rubio G, Martinez I, Ponce G et al (2006) Long-acting injectable risperidone compared with zuclopenthixol in the treatment of schizophrenia with substance abuse comorbidity. Can J Psychiatry 51(8):531–539
Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Moller HJ (2006) World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, Part 2: long-term treatment of schizophrenia. World J Biol Psychiatry 7(1):5–40
Khantzian EJ (1997) The self-medication hypothesis of substance use disorders: A reconsideration and recent applications. Harv Rev Psychiatry 4:231–244
Siris SG, Mason SE, Bermanzohn PC et al (1993) Dual diagnosis/psychiatric comorbidity of drug dependence: epidemiology and treatment. Adjunctive imipramine in substance-abusing dysphoric schizophrenic patients. Psychopharmacol Bull 29:127–133
Wilkins JN (1997) Pharmacotherapy of schizophrenia patients with comorbid substance abuse. Schizophr Bull 23:215–228
Ziedonis DM, Richardson T, Lee E et al (1992) Adjunctive desipramine in the treatment of cocaine abusing schizophrenics. Psychopharmacol Bull 28:309–314
Kalyoncu A, Mirsal H, Pektas O et al (2005) Use of lamotrigine to augment clozapine in patients with resistant schizophrenia and comorbid alcohol dependence: a potent anti-craving effect? J Psychopharmacol 19(3):301–305
Gold MS, Donabedian RK, Dillard M et al (1978) Antipsychotic effect opiate agonists. Lancet 2:398–399
Sernyak MJ, Glazer WM, Heninger GR et al (1998) Naltrexone augmentation of neuroleptics in schizophrenia. J Clin Psychopharmacol 18(3):248–251
Petrakis IL, O’Malley S, Rounsaville B et al (2004) Naltrexone augmentation of neuroleptic treatment in alcohol abusing patients with schizophrenia. Psychopharmacology (Berl) 172(3):291–297
Maxwell S, Shinderman MS (2000) Use of naltrexone in the treatment of alcohol use disorders in patients with concomitant major mental illness. J Addict Dis 19:61–69
Batki SL, Dimmock JA, Wade M et al (2007) Monitored naltrexone without counselling for alcohol abuse/dependence in schizophrenia-spectrum disorders. Am J Addict 16:253–259
Kofoed L, Kania J, Walsh T, Atkinson RM (1986) Outpatient treatment of patients with substance abuse and coexisting psychiatric disorders. Am J Psychiatry 143:867–872
Mueser KT, Noordsy DL, Fox L, Wolfe R (2003) Disulfiram treatment for alcoholism in severe mental illness. Am J Addict 12(3):242–252
Ewing JA, Meuller RA, Rouse BA, Silver D (1977) Low levels of dopamine-beta-hydroxylase and psychosis. Am J Psychiatry 134:927–928
Major LF, Lerner P, Ballenger JC et al (1978) Dopamine-β-hydroxylase in the cerebrospinal fluid: relationship to disulfiram-induced psychosis. Biol Psychiatry 14:337–343
Gawin FH (1986) Neuroleptic reduction of cocaine-induced paranoia but not euphoria? Psychopharmacology 90:142–143
Richard ML, Liskow BI, Perry PJ (1985) Recent psychostimulant use in hospitalized schizophrenics. J Clin Psychiatry 46:79–83
Siris SG (1990) Pharmacological treatment of substance-abusing schizophrenic patients. Schizophr Bull 16:111–122
Green AI (2005) Schizophrenia and comorbid substance use disorder: effects of antipsychotics. J Clin Psychiatry 66(Suppl 6):21–26
Noordsy DL, Green AI (2003) Pharmacotherapy for schizophrenia and co-occuring substance use disorders. Curr Psychiatry Rep 5:340–346
Wobrock T, Soyka M (2008) Pharmacotherapy of schizophrenia with comorbid substance use disorder-Reviewing the evidence and clinical recommendations. Prog Neuropsychopharmacol Biol Psychiatry 32(6):1375–1385
Potvin S, Stip E, Roy JY (2003) Clozapine, quetiapine and olanzapine among addicted schizophrenic patients: towards testable hypotheses. Int Clin Psychopharmacol 18:121–132
Lacro JP, Dunn LB, Dolder CR et al (2002) Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry 63:892–909
Chambers RA, Krystal JH, Self DW (2001) A neurobiological basis for substance abuse comorbidity in schizophrenia. Biol Psychiatry 50:71–83
Roesner S, Leucht S, Lehert P, Soyka M (2008) Acamprosate supports abstinence, naltrexone prevents excessive drinking: evidence from a meta-analysis with unreported outcomes. J Psychopharmacol 22(1):11–23
Ballenger JC, Post RM (1984) Carbamazepine in alcohol withdrawal syndromes and schizophrenic psychoses. Psychopharmacol Bull 20(3):572–584
Olivera AA, Kiefer MW, Manley NK (1990) Tardive dyskinesia in psychiatric patients with substance abuse. Am J Alcohol Abuse 16:57–66
Farren CK, Hameedi FA, Rosen MA et al (2000) Significant interaction between clozapine and cocaine in cocaine addicts. Drug Alc Depens 59:153–163
Carey KB (1997) Reliability and validity of the time-line follow-back interview among psychiatric outpatients: a preliminary report. Psychol Addict Behav 11:26–33
Prochaska JO, DiClemente CC, Norcross JC (1992) In search of how people change: applications to addictive behaviors. Am Psychol 47:1102–1114
Ziedonis DM, Trudeau K (1997) Motivation to quit using substances among individuals with schizophrenia: Implications for a motivation-based treatment model. Schizophr Bull 23:229–238
Barrowclough C, Haddock G, Tarrier N, Lewis SW, Moring J, O’Brien R (2001) Randomizied controlled trial of motivational interviewing, cognitive behavior therapy, and family intervention for patients with comorbid schizophrenia and substance use disorders. Am J Psychiatry 158:1706–1713
Miller WR (1983) Motivational interviewing. Behav Psychotherapy 11:147–172
Miller WR, Zweben A, DiClemente CC et al (1995) Motivational enhancement therapy manual. US Department of Health and Human Services, Rockville, MD, NIH Publication No. 94–3723
Miller WR, Rollnick S (2002) Motivational interviewing: preparing people to change, 2nd edn. Guilford, New York, NY
Drake RE, Mueser KT, Brunette MF, McHugo GJ (2004) A review of treatments for people with severe mental illnesses and co-occurring substance use disorders. Psychiatr Rehabil J Spring, 27(4):360–374
Martino S, Carroll KM, Nich C, Rounsaville BJ (2006) A randomized controlled pilot study of motivational interviewing for patients with psychotic and drug use disorders. Addiction 101(10):1479–1492
Edwards J, Elkins K, Hinton M, Harrigan SM, Donovan K, Athanasopoulos O, McGorry PD (2006) Randomized controlled trial of a cannabis-focused intervention for young people with first-episode psychosis. Acta Psychiatr Scand 114(2):109–117
Hjorthøj C, Fohlmann A, Nordentoft M (2009) Treatment of cannabis use disorders in people with schizophrenia spectrum disorders – a systematic review. Addict Behav 34(6–7):520–525
Addington J, Addington D (2001) Impact of an early psychosis program on substance use. Psychiatr Rehabil J 25(1):60–67
Baker A, Bucci S, Lewin TJ, Kay-Lambkin F, Constable PM, Carr VJ (2006) Cognitive-behavioural therapy for substance use disorders in people with psychotic disorders: Randomised controlled trial. Br J Psychiatry 188:439–448
Craig TK, Johnson S, McCrone P, Afuwape S, Hughes E, Gournay K, White I, Wanigaratne S, Leese M, Thornicroft G (2008) Integrated care for co-occurring disorders: psychiatric symptoms, social functioning, and service costs at 18 months. Psychiatr Serv 59(3):276–282
Shaner A, Eckman T, Roberts LJ, Fuller T (2003) Feasibility of a skills training approach to reduce substance dependence among individuals with schizophrenia. Psychiatr Serv 54(9):1287–1289
Roberts LJ, Eckman TA, Shaner A (1999) Overcoming addictions: skills training for people with schizophrenia. Norton Professional Books, New York
Ziedonis DM, Stern R (2001) Dual recovery therapy for schizophrenia and substance abuse. Psychiatr Ann 31(4):255–264
Bellack AS, DiClemente CC (1999) Treating substance abuse among patients with schizophrenia. Psychiatr Serv 50(1):75–80
D’Amelio R, Behrendt B, Wobrock T (2007) Psychoeducation schizophrenia and substance abuse. Elsevier, Amsterdam
Gouzoulis-Mayfrank E (2004) Dual diagnosis of psychosis and addiction. From principles to practice. Nervenarzt 75(7):642–650
Drake RE, McHugo GJ, Clark RE, Teague GB, Xie H, Miles K, Ackerson TH (1998) Assertive community treatment for patients with co-occurring severe mental illness and substance use disorder: a clinical trial. Am J Orthopsychiatry 68(2):201–215
Essock SM, Mueser KT, Drake RE, Covell NH, McHugo GJ, Frisman LK, Kontos NJ, Jackson CT, Townsend F, Swain K (2006) Comparison of ACT and standard case management for delivering integrated treatment for co-occurring disorders. Psychiatr Serv 57(2):185–196
Morse GA, Calsyn RJ, Dean Klinkenberg W, Helminiak TW, Wolff N, Drake RE, Yonker RD, Lama G, Lemming MR, McCudden S (2006) Treating homeless clients with severe mental illness and substance use disorders: costs and outcomes. Commun Ment Health J 42(4):377–404
Lehman AF, Herron JD, Schwartz RP, Myers CP (1993) Rehabilitation for adults with severe mental illness and substance use disorders. A clinical trial. J Nerv Ment Dis 181(2):86–90
Meisler N, Blankertz L, Santos AB, McKay C (1997) Impact of assertive community treatment on homeless persons with co-occurring severe psychiatric and substance use disorders. Commun Ment Health J 33(2):113–122
Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimarães FS (2006) Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39(4):421–429
Yovell Y, Opler LA (1994) Clozapine reverses cocaine craving in a treatment-resistant mentally ill chemical abuser: a case report and a hypothesis. J Nerv Ment Dis 182(10):591–592
Buckley PF (1998) Novel antipsychotic medications and the treatment of comorbid substance abuse in schizophrenia. J Subst Abuse Treat 15(2):113–116
Tsuang JW, Eckman TE, Shaner A, Marder SR (1999) Clozapine for substance-abusing schizophrenic patients. Am J Psychiatry 156(7):1119–1120
Brown ES, Nejtek VA, Perantie DC, Bobadilla L (2002) Quetiapine in bipolar disorder and cocaine dependence. Bipolar Disord 4(6):406–411
Albanese MJ (2001) Safety and efficacy of risperidone in substance abusers with psychosis. Am J Addict 10(2):190–191
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Wobrock, T., Czesnik, D., Malchow, B. (2011). Schizophrenia and Comorbid Substance Abuse – Pathophysiological and Therapeutic Approaches. In: Ritsner, M. (eds) Handbook of Schizophrenia Spectrum Disorders, Volume III. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0834-1_15
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