Neurotoxicity Research

, Volume 10, Issue 3–4, pp 235–252 | Cite as

The vulnerability to alcohol and substance abuse in individuals diagnosed with schizophrenia

  • John H. Krystal
  • D. Cyril D’Souza
  • JÜrgen Gallinat
  • Naomi Driesen
  • Anissa Abi-Dargham
  • Ismene Petrakis
  • Andreas Heinz
  • Godfrey Pearlson
Article

Abstract

Individuals with schizophrenia are at increased risk for developing substance abuse disorders. Here, we consider factors that might elevate their risk for substance abuse. The tendency among schizophrenic individuals to overvalue drug-like rewards and to devalue the potential negative consequences of substance abuse may be a contributing factor to their substance abuse risk. This bias, which may partly reflect the convergence of glutamatergic and dopaminergic input to the limbicstriatum, also may contribute to disadvantageous decision-making and other impulsive behavior. This propensity to seek drug-like rewards is augmented by alterations in nicotinic cholinergic, GABAergic, glutamatergic, and cannabinnoid receptor function associated with schizophrenia that increase the abuse liability of low doses of nicotine,ethanol, and perhaps cannabis, and augment the dysphoric effects of higher doses of ethanol and cannabis. The distortions in reward processing and altered response to substances of abuse also increase the likelihood that individuals with schizophrenia will self-medicate their subjective distress with abused substances. The focus on distinctions between motivation and reward with respect to substance abuse risk by schizophrenic patients suggests a need for a reconsideration of the construct of “negative symptoms” for this duallydiagnosed patient group.

Keywords

Schizophrenia Alcoholism Substance abuse Frontal cortex Hippocampus Striatum Glutamate Dopamine GABA Vulnerability Dual-diagnosis 

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References

  1. Abi-Dargham A, R Gil, J Krystal, RM Baldwin, JP Seibyl, M Bowers, CH van Dyck, DS Charney, RB Innis and M Laruelle (1998) Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort.Am. J. Psychiatry 155, 761–767.PubMedGoogle Scholar
  2. Abi-Dargham A, J Rodenhiser, D Printz, Y Zea-Ponce, R Gil, LS Kegeles, R Weiss, TB Cooper, JJ Mann, RL Van Heertum, JM Gorman and M Lamelle (2000) From, the cover: increased baseline occupancy of D2 receptors by dopamine in schizophrenia.Proc. Natl. Acad. Sci. USA. 97, 8104–8109.PubMedCrossRefGoogle Scholar
  3. Abi-Dargham A, LS Kegeles, D Martinez, RB Innis and M Laruelle (2003) Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naive healthy volunteers: results from a large cohort.Eur. Neuropsychopharmacol. 13, 459–468.PubMedCrossRefGoogle Scholar
  4. Anthony JC, LA Warner and RC Kessler (1994) Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey.Exp. Clin. Psychopharmacol. 2, 244–268.CrossRefGoogle Scholar
  5. Baron M, R Gruen, JD Rainer, J Kane, L Asnis and S Lord (1985) A family study of schizophrenic and normal control probands: implications for the spectrum concept of schizophrenia.Am. J. Psychiatry 142, 477–455.Google Scholar
  6. Bartels SJ, GB Teague, RE Drake, RE Clark, PW Bush and DL Noordsy (1993) Substance abuse in schizophrenia: service utilization and costs.J. Nerv. Ment. Dis. 181, 227–232.PubMedCrossRefGoogle Scholar
  7. Bechara A, H Damasio and AR Damasio (2000a) Emotion, decision making and the orbitofrontal cortex.Cereb. Cortex. 10, 295–307.PubMedCrossRefGoogle Scholar
  8. Bechara A, D Tranel and H Damasio (2000b) Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions.Brain 123, 2189–2202.PubMedCrossRefGoogle Scholar
  9. Bechara A, S Dolan, N Denburg, A Hindes, SW Anderson and PE Nathan (2001) Decision-making deficits, linked to a dysfunctional ventromedial prefrontal cortex, revealed in alcohol and stimulant abusers.Neuropsychologia 39, 376–389.PubMedCrossRefGoogle Scholar
  10. Bechara A, S Dolan and A Hindes (2002) Decision-making and addiction (part II): myopia for the future or hypersensitivity to reward?Neuropsychologia 40, 1690–1705.PubMedCrossRefGoogle Scholar
  11. Beninger RJ, J Wasserman, K Zanibbi, D Charbonneau, J Mangels and BV Beninger (2003) Typical and atypical antipsychotic medications differentially affect two nondeclarative memory tasks in schizophrenic patients: a double dissociation.Schizophr. Res. 61, 281–292.PubMedCrossRefGoogle Scholar
  12. Bidaut-Russell M, EM Smith and SE Bradford (1994) Gender differences in lifetime psychiatric disorders between sons and daughters of alcoholic mothers: a pilot study.Alcoholism, Clin. Exp. Res. 18, 244–247.CrossRefGoogle Scholar
  13. Bilder RM, B Bogerts, M Ashtari, H Wu, JM Alvir, D Jody, G Reiter, L Bell and JA Lieberman (1995) Anterior hippocam pal volume reductions predict frontal lobe dysfunction in first episode schizophrenia.Schizophr. Res. 17, 47–58.PubMedCrossRefGoogle Scholar
  14. Bjork JM, B Knutson, GW Fong, DM Caggiano, SM Bennett and DW Hommer (2004) Incentive-elicited brain activation in adolescents: similarities and differences from young adults.J. Neurosci 24, 1793–1802.PubMedCrossRefGoogle Scholar
  15. Blanchard JJ, SA Brown, WP Horan and AR Sherwood (2000) Substance use disorders in schizophrenia: review, integration, and a proposed model.Clin. Psychol. Rev. 20, 207–234.PubMedCrossRefGoogle Scholar
  16. Brecher M and H Begleiter (1983) Event-related brain potentials to high-incentive stimuli in unmedicated schizophrenic patients.Biol Psychiatry 18, 661–674.PubMedGoogle Scholar
  17. Breese CR, MJ Lee, CE Adams, B Sullivan, J Logel, KM Gillen, MJ Marks, AC Collins and S Leonard (2000) Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia.Neuropsychopharmacol 23, 351–364.CrossRefGoogle Scholar
  18. Breier A, TP Su, R Saunders, RE Carson, BS Kolachana, A de Bartolomeis, DR Weinberger, N Weisenfeld, AK Malhotra, WC Eckelman and D Pickar (1997) Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from, a novel positron emission tomography method.Proc. Natl. Acad. Sci. USA 94, 2569- 2574.PubMedCrossRefGoogle Scholar
  19. Brunette MF, KT Mueser, H Xie and RE Drake (1997) Relationships between symptoms of schizophrenia and substance abuse.J. Nerv. Ment. Dis. 185, 13–20.PubMedCrossRefGoogle Scholar
  20. Bryson G, M Bell, E Kaplan, T Greig and P Lysaker (1998) Affect recognition in deficit syndrome schizophrenia.Psychiatry Res. 77, 113–120.PubMedCrossRefGoogle Scholar
  21. Bussey TJ, BJ Everitt and TW Robbins (1997) Dissociable effects of cingulate and medial frontal cortex lesions on stimulus-reward learning using a novel Pavlovian autoshaping procedure for the rat: implications for the neurobiology of emotion.Behav. Neurosci 111, 908–919.PubMedCrossRefGoogle Scholar
  22. Cantor-Graae E, LG Nordstrom and TF McNeil (2001) Substance abuse in schizophrenia: a review of the literature and a study of correlates in Sweden.Schizophr. Res. 48, 69–82.PubMedCrossRefGoogle Scholar
  23. Cardinal RN, JA Parkinson, J Hall and BJ Everitt (2002) Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci. Biobehav. Rev.26, 321–352.PubMedCrossRefGoogle Scholar
  24. Carpenter WT Jr, DW Heinrichs and AM Wagman (1988) Deficit and nondeficit forms of schizophrenia: the concept.Am. J. Psychiatry 145, 578–583.PubMedGoogle Scholar
  25. Chambers RA, JH Krystal and DW Self (2001) A neurobiological basis for substance abuse comorbidity in schizophrenia.Biol. Psychiatry 50, 71–83.PubMedCrossRefGoogle Scholar
  26. Clark DB, J Cornelius, DS Wood and M Vanyukov (2004) Psychopathology risk transmission in children of parents with substance use disorders.Am. J. Psychiatry 161, 685–691.PubMedCrossRefGoogle Scholar
  27. Cohen BD (1956) Motivation and performance in schizophrenia.J. Abnormal Social Psychol. 52, 186–190.CrossRefGoogle Scholar
  28. Crespo-Facorro B, S Paradiso, NC Andreasen, DS O’Leary, GL Watkins, LL Ponto and RD Hichwa (2001) Neural mechanisms of anhedonia in schizophrenia: a PET study of response to unpleasant and pleasant odors.JAMA 286, 427–435.PubMedCrossRefGoogle Scholar
  29. Cromwell HC and W Schultz (2003) Effects of expectations for different reward magnitudes on neuronal activity in primate striatum.J. Neurophysiol. 89, 2823–2838.PubMedCrossRefGoogle Scholar
  30. D’Souza DC, WM Abi-Saab, S Madonick, K Forselius-Bielen, A Doersch, G Braley, R Gueorguieva, TB Cooper and JH Krystal (2005) Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction.Biol. Psychiatry 57, 594–608.PubMedCrossRefGoogle Scholar
  31. Dao-Castellana MH, ML Paillere-Martinot, P Hantraye, D Attar-Levy, P Remy, C Crouzel, E Artiges, A Feline, A Syrota and JL Martinot (1997) Presynaptic dopaminergic function in the striatum of schizophrenic patients.Schizophr. Res. 23, 167–174.PubMedCrossRefGoogle Scholar
  32. Deakin JF and MD Simpson (1997a) A two-process theory of schizophrenia: evidence from studies inpost-mortem brain.J. Psychiatric Res. 31, 277–295.CrossRefGoogle Scholar
  33. Deakin JF and MD Simpson (1997b) A two-process theory of schizophrenia: evidence from studiesin post-mortem brain.J. Psychiatric Res. 31, 277–295.CrossRefGoogle Scholar
  34. DeQuardo JR, CF Carpenter and R Tandon (1994) Patterns of substance abuse in schizophrenia: nature and significance.J. Psychiatric Res. 28, 267–275.CrossRefGoogle Scholar
  35. Dervaux A, FJ Bayle, X Laqueille, MC Bourdel, MH Le Borgne, JP Olie and MO Krebs (2001) Is substance abuse in schizophrenia related to impulsivity, sensation seeking, or anhedonia?Am. J. Psychiatry 158, 492–494.PubMedCrossRefGoogle Scholar
  36. Dervaux A, FJ Bayle, X Laqueille, MC Bourdel, MH Le Borgne, JP Olie and MO Krebs (2004) Nicotine use in schizophrenia and disinhibition.Psychiatry Res. 128, 229- 234.PubMedCrossRefGoogle Scholar
  37. Dixon L (1999) Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on outcomes.Schizophr. Res. 35, S93-S100.PubMedCrossRefGoogle Scholar
  38. Dixon L, G Haas, P Weiden, J Sweeney and A Frances (1990) Acute effects of drug abuse in schizophrenic patients: clinical observations and patients’ self-reports.Schizophr. Bull. 16, 69–79.PubMedGoogle Scholar
  39. Dixon L, G Haas, PJ Weiden, J Sweeney and AJ Frances (1991) Drug abuse in schizophrenic patients: clinical correlates and reasons for use.Am. J. Psychiatry 148, 224–230.PubMedGoogle Scholar
  40. Drake RE, MA Wallach, HS Alverson and KT Mueser (2002) Psychosocial aspects of substance abuse by clients with severe mental illness.J. Nerv. Ment. Dis. 190, 100–106.PubMedCrossRefGoogle Scholar
  41. Duke PJ, C Pantelis, MA McPhillips and TR Barnes (2001) Comorbid non-alcohol substance misuse among people with schizophrenia: epidemiological study in central London.Brit. J. Psychiatry 179, 509–513.CrossRefGoogle Scholar
  42. Elkashef AM, D Doudet, T Bryant, RM Cohen, SH Li and RJ Wyatt (2000) 6-[18F]DOPA PET study in patients with schizophrenia. Positron emission tomography.Psychiatry Res. 100, 1–11.PubMedCrossRefGoogle Scholar
  43. Epstein EE, BE Ginsburg, VM Hesselbrock and JC Schwarz (1994) Alcohol and drug abusers subtyped by antisocial personality and primary or secondary depressive disorder.Ann. NY Acad. Sci. 708, 187–201.PubMedCrossRefGoogle Scholar
  44. Erlenmeyer-Kimling L, UH Adamo, D Rock, SA Roberts, AS Bassett, E Squires-Wheeler, BA Cornblatt, J Endicott, S Pape and II Gottesman (1997) The New York High-Risk Project. Prevalence and comorbidity of axis I disorders in offspring of schizophrenic parents at 25-year follow-up.Arch. Gen. Psychiatry 54, 1096–1102.PubMedGoogle Scholar
  45. Everitt BJ, JA Parkinson, MC Olmstead, M Arroyo, P Robledo and TW Robbins (1999) Associative processes in addiction and reward. The role of amygdala-ventral striatal subsystems.Ann. NY Acad. Sci. 877, 412–438.PubMedCrossRefGoogle Scholar
  46. Fenton WS and TH McGlashan (1994) Antecedents, symptom progression, and long-term outcome of the deficit syndrome in schizophrenia.Am. J. Psychiatry 151, 351–356.PubMedGoogle Scholar
  47. Fenton WS, CR Blyler and RK Heinssen (1997) Determinants of medication compliance in schizophrenia: empirical and clinical findings.Schizophr. Bull. 23, 637–651.PubMedGoogle Scholar
  48. Fiorillo CD, PN Tobler and W Schultz (2003) Discrete coding of reward probability and uncertainty by dopamine neurons.Science 299, 1898–1902.PubMedCrossRefGoogle Scholar
  49. Fowler RC, MT Tsuang, RJ Cadoret and E Monnelly (1975) Non-psychotic disorders in the families of process of schizophrenics.Acta Psychiatr. Scand. 51, 153–160.PubMedCrossRefGoogle Scholar
  50. Freedman R, S Leonard, JM Gault, J Hopkins, CR Cloninger, CA Kaufmann, MT Tsuang, SV Farone, D Malaspina, DM Svrakic, A Sanders and P Gejman (2001) Linkage disequilibrium for schizophrenia at the chromosome 15q l3-14 locus of the α7nicotinic acetylcholine receptor subunit gene (CHRNA7).Am. J. Med Genet. 105, 20–22.PubMedCrossRefGoogle Scholar
  51. Freudenreich O, C Gather, AE Evins, DC Henderson and DC Goff (2004) Attitudes of schizophrenia outpatients toward psychiatric medications: relationship to clinical variables and insight.J. Clin. Psychiatry 65, 1372–1376.PubMedCrossRefGoogle Scholar
  52. Frye MA, LL Altshuler, SL McElroy, T Suppes, PE Keck, K Denicoff, WA Nolen, R Kupka, GS Leverich, C Pollio, H Grunze, J Waiden and RM Post (2003) Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder.Am. J. Psychiatry 160, 883–889.PubMedCrossRefGoogle Scholar
  53. Galen LW, KJ Brower, BW Gillespie and RA Zucker (2000) Sociopathy, gender, and treatment outcome among outpatient substance abusers.Drug Alcohol Depend. 61, 23–33.PubMedCrossRefGoogle Scholar
  54. Gao XM, K Sakai, RC Roberts, RR Conley, B Dean and CA Tamminga (2000) lonotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia.Am. J. Psychiatry 157, 1141–1149.PubMedCrossRefGoogle Scholar
  55. Garmezy N (1952) Stimulus differentiation by schizophrenic and normal subjects under conditions of reward and punishment.J. Personality 20, 253–276.PubMedCrossRefGoogle Scholar
  56. Gearon JS, AS Bellack, J Rachbeisel and L Dixon (2001) Drug-use behavior and correlates in people with schizophrenia.Addict. Behav. 26, 51–61.PubMedCrossRefGoogle Scholar
  57. Gearon JS, SI Kaltman, C Brown and AS Bellack (2003) Traumatic life events and PTSD among women with substance use disorders and schizophrenia.Psychiatr. Serv. 54, 523–528.PubMedCrossRefGoogle Scholar
  58. George TP, JC Vessicchio, A Termine, DM Sahady, CA Head, WT Pepper, TR Kosten and BE Wexler (2002) Effects of smoking abstinence on visuospatial working memory function in schizophrenia.Neuropsychopharmacol. 26, 75–85.CrossRefGoogle Scholar
  59. Gershon ES, LE DeLisi, J Hamovit, JI Nurnberger Jr. ME Maxwell, J Schreiber, D Dauphinais, CW Dingman 2nd and JJ Guroff (1988) A controlled family study of chronic psychoses. Schizophrenia and schizoaffective disorder.Arch. Gen Psychiatry 45, 328–336.PubMedGoogle Scholar
  60. Goldstein RZ, ND Volkow, GJ Wang, JS Fowler and S Rajaram (2001) Addiction changes orbitofrontal gyrus function: involvement in response inhibition.Neuroreport 12, 2595–2999.PubMedCrossRefGoogle Scholar
  61. Goswami S, SK Mattoo, D Basu and G Singh (2004) Substanceabusing schizophrenics: do they self-medicate?Am. J. Addict 13, 139–150.PubMedCrossRefGoogle Scholar
  62. Goto Y and P O’Donnell (2002) Delayed mesolimbic system alteration in a developmental animal model of schizophrenia.J. Neurosci. 22, 9070–9077.PubMedGoogle Scholar
  63. Grant KA and G Colombo (1993) Discriminative stimulus effects of ethanol: effect of training dose on the substitution ofN-methyl-D-aspartate antagonists.J. Pharmacol Exp. Ther 264, 1241–1247.PubMedGoogle Scholar
  64. Green AI, SV Zimmet, RD Strous and JJ Schildkraut (1999) Clozapine for comorbid substance use disorder and schizophrenia: do patients with schizophrenia have a primary reward-deficiency syndrome that can be ameliorated by clozapine?Harvard Rev. Psychiatry 6, 287–296.CrossRefGoogle Scholar
  65. Hafner H, K Maurer, G Trendler, Wan der Heiden, M Schmidt and R Konnecke (2005) Schizophrenia and depression: challenging the paradigm of two separate diseases - a controlled study of schizophrenia, depression and healthy controls.Schizophr. Res. 77, 11–24.PubMedCrossRefGoogle Scholar
  66. Heath AC, PA Madden, KK Bucholz, SH Dinwiddie, WS Slutske, LJ Bierut, JW Rohrbaugh, DJ Statham, MP Dunne, JB Whitfield and NG Martin (1999) Genetic differences in alcohol sensitivity and the inheritance of alcoholism risk.Psychol Med. 29, 1069–1081.PubMedCrossRefGoogle Scholar
  67. Heinz A (1999) [Psychopathological correlates of dopaminergic dysfunction in alcoholic and schizophrenic patients].Nervernarzt. 70, 399–407.CrossRefGoogle Scholar
  68. Heinz A, S Lober, A Georgi, J Wrase, D Hermann, ER Rey, S Wellek and K Mann (2003) Reward craving and withdrawal relief craving: assessment of different motivational pathways to alcohol intake.Alcohol Alcoholism 38, 35–39.CrossRefGoogle Scholar
  69. Heinz A, T Siessmeier, J Wrase, D Hermann, S Klein, SM Grusser-Sinopoli, H Flor, DF Braus, HG Buchholz, G Grunder, M Schreckenberger, MN Smolka, F Rosch, K Mann and P Bartenstein (2004) Correlation between dopamine D2 receptors in the ventral striatum and central processing of alcohol cues and craving.Am. J. Psychiatry 161, 1783–1789.PubMedCrossRefGoogle Scholar
  70. Heinz A, T Siessmeier, J Wrase, HG Buchholz, G Grander, Y Kumakura, P Gumming, M Schreckenberger, MN Smolka, F Rosch, K Mann and P Bartenstein (2005) Correlation of alcohol craving with striatal dopamine synthesis capacity and D2/3 receptor availability: a combined [18 F]DOPA and [F]DMFP PET study in detoxified alcoholic patients.Am. J Psychiatry 162, 1515–1520.PubMedCrossRefGoogle Scholar
  71. Hesselbrock MN and VM Hesselbrock (1992) Relationship of family history, antisocial personality disorder and personality traits in young men at risk for alcoholism.J. Studies Alcohol 53, 619–625.Google Scholar
  72. Hommer DW, B Knutson, GW Fong, S Bennett CM Adams and JL Varnera (2003) Amygdalar recruitment during anticipation of monetary rewards: an event-related fMRI study.Ann. NYAcad Sci. 985, 476–478.Google Scholar
  73. Hurwitz T, L Kopala, C Clark and B Jones (1988) Olfactory deficits in schizophrenia.Biol. Psychiatry 23, 123–128.PubMedCrossRefGoogle Scholar
  74. Jacobsen LK, DC D’Souza, WE Mend, KR Pugh, P Skudlarski and JH Krystal (2004) Nicotine effects on brain function and functional connectivity in schizophrenia.Biol. Psychiatry 55, 850–858.PubMedCrossRefGoogle Scholar
  75. Juckel G, L Sass and A Heinz (2003) Anhedonia, self-experience in schizophrenia, and implications for treatment.Pharmacopsychia-try 36, S176-S180.Google Scholar
  76. Juckel G, F Schlagenhauf, M Koslowski, T Wüstenberg, A Villringer, B Knutson, J Wrase and A Heinz(2005) Dysfunction of ventral striatal reward prediction in schizophrenia.Neuroimage E-publication ahead of print.Google Scholar
  77. Kapur S, RB Zipursky and G Remington (1999) Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzepine in schizophrenia.Am. J. Psychiatry 156, 286–293.PubMedGoogle Scholar
  78. Kavanagh DJ, J McGrath, JB Saunders, G Dore and D Clark (2002) Substance misuse in patients with schizophrenia: epidemiology and management.Drugs 62, 743–755.PubMedCrossRefGoogle Scholar
  79. Kegeles LS, DC Shungu, S Anjilvel, S Chan, SP Ellis, E Xanthopoulos, D Malaspina, JM Gorman, JJ Mann, M Lamelle and CA Kaufmann (2000) Hippocampal pathology in schizophrenia: magnetic resonance imaging and spectros- copy studies.Psychiatiy Res. 98, 163–175.CrossRefGoogle Scholar
  80. Kendler KS (1985) A twin study of individuals with both schizophrenia and alcoholism.Brit. J. Psychiatry 147, 48–53.CrossRefGoogle Scholar
  81. Kendler KS and CO Gardner (1997) The risk for psychiatric disorders in relatives of schizophrenic and control probands: a comparison of three independent studies.Psychol Med. 27,411–419.PubMedCrossRefGoogle Scholar
  82. Kendler KS and P Hays (1983) Schizophrenia subdivided by the family history of affective disorder. A comparison of symptomatology and course of illness.Arch. Gen. Psychiatry 40, 951–955.PubMedGoogle Scholar
  83. Kendler KS, AM Gruenberg and JS Strauss (1981) An independent analysis of the Copenhagen sample of the Danish adoption study of schizophrenia. I. The relationship between anxiety disorder and schizophrenia.Arch. Gen. Psychiatry 38, 973–977.PubMedGoogle Scholar
  84. Kendler KS, AM Gruenberg and JS Strauss (1982) An independent analysis of the Copenhagen sample of the Danish adoption study of schizophrenia. IV. The relationship between major depressive disorder and schizophrenia.Arch. Gen. Psychiatry 39, 639–642.PubMedGoogle Scholar
  85. Kendler KS, AM Gruenberg and MT Tsuang (1985a) Psychiatric illness in first-degree relatives of schizophrenic and surgical control patients. A family study using DSM-III criteria.Arch. Gen. Psychiatry 42, 770–779.PubMedGoogle Scholar
  86. Kendler KS, CC Masterson and KL Davis (1985b) Psychiatric illness in first-degree relatives of patients with paranoid psychosis, schizophrenia and medical illness.Brit. J. Psychiatry 147, 524–531.CrossRefGoogle Scholar
  87. Kendler KS, M McGuire, AM Gruenberg, A O’Hare, M Spellman and D Walsh (1993) The Roscommon Family Study. IV. Affective illness, anxiety disorders, and alcohol ism in relatives.Arch. Gen. Psychiatry 50, 952–960.PubMedGoogle Scholar
  88. Kendler KS, M McGuire, AM Gruenberg and D Walsh (1994) Clinical heterogeneity in schizophrenia and the pattern of psychopathology in relatives: results from an epidemiologically based family study.Acta Psychiatr. Scand. 89, 294–300.PubMedCrossRefGoogle Scholar
  89. Kendler KS, M McGuire, AM Gruenberg and D Walsh (1995) Examining the validity of DSM-III-R schizoaffective disorder and its putative subtypes in the Roscommon Family Study.Am. J. Psychiatry 152, 755–764.PubMedGoogle Scholar
  90. Kendler KS, L Karkowski-Shuman and D Walsh (1996) The risk for psychiatric illness in siblings of schizophrenics: the impact of psychotic and non-psychotic affective illness and alcoholism in parents.Acta Psychiatr. Scand. 94, 49–55.PubMedCrossRefGoogle Scholar
  91. Khantzian EJ (1997) The self-medication hypothesis of substance use disorders: a reconsideration and recent applications [see comments].Harvard Rev. Psychiatiy 4, 231–244.CrossRefGoogle Scholar
  92. Khantzian EJ, JE Mack and AF Schatzberg (1974) Heroin use as an attempt to cope: clinical observations.Am. J. Psychiatry 131, 160–164.PubMedGoogle Scholar
  93. Kirkpatrick B, XF Amador, M Flaum, SA Yale, JM Gorman, WT Carpenter Jr, M Tohen and T McGlashan (1996) The deficit syndrome in the DSM-IV Field Trial: I. Alcohol and other drug abuse.Schizophr. Res. 20, 69–77.PubMedCrossRefGoogle Scholar
  94. Knutson B, CM Adams, GW Fong and D Hommer (2001a) Anticipation of increasing monetary reward selectively recruits nucleus accumbens.J. Neurosci. 21, RC159.PubMedGoogle Scholar
  95. Knutson B, GW Fong, CM Adams, JL Varner and D Hommer (2001b) Dissociation of reward anticipation and outcome with event-related fMRI.Neuroreport 12, 3683–3687.PubMedCrossRefGoogle Scholar
  96. Knutson B, GW Fong, CM Adams, JL Varner and D Hommer (2001c) Dissociation of reward anticipation and outcome with event-related fMRI.Neuroreport 12, 3683–3687.PubMedCrossRefGoogle Scholar
  97. Knutson B, GW Fong, SM Bennett, CM Adams and D Hommer (2003) A region of mesial prefrontal cortex tracks monetarily rewarding outcomes: characterization with rapid event-related fMRI.Neuroimage 18, 263–272.PubMedCrossRefGoogle Scholar
  98. Knutson B, JM Bjork, GW Fong, D Hommer, VS Mattay and DR Weinberger (2004) Amphetamine modulates human incentive processing.Neuron 43, 261–269.PubMedCrossRefGoogle Scholar
  99. Krystal H and HA Raskin (1970)Drug Dependence: Aspects of Ego Functions (Wayne State University Press:Wayne State University).Google Scholar
  100. Krystal JH, IL Petrakis, E Webb, NL Cooney, LP Karper, S Namanworth, P Stetson, LA Trevisan and DS Charney (1998) Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics.Arch. Gen. Psychiatry 55, 354–360.PubMedCrossRefGoogle Scholar
  101. Krystal JH, DC D’Souza, S Madonick and IL Petrakis (1999) Toward a rational pharmacotherapy of comorbid substance abuse in schizophrenic patients.Schizophr. Res. 35 suppl, S35–S49.Google Scholar
  102. Krystal JH, JA Cramer, W Kroll, G Kirk, RA Rosenheck and Group VANCS (2001) Naltrexone in the treatment of alcohol dependence.N Engl. J. Med 345, 1734–1739.PubMedCrossRefGoogle Scholar
  103. Krystal JH and B Tabakoff (2002) Ethanol abuse, dependence, and withdrawal: neurobiology and clinical implications, In:Psychopharmacology: a Fifth Generation of Progress (Davis KL, DS Charney, JT Coyle and C Nemeroff, Eds.) (Lippincott Williams and Wilkins: Philadelphia), pp 1425- 1443.Google Scholar
  104. Krystal JH, DC D’Souza, D Mathalon, E Perry, A Beiger and RE Hoffman (2003 a) NMD A receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development.Psychopharmacology 169, 215–233.PubMedCrossRefGoogle Scholar
  105. Krystal JH, IL Petrakis, D Limoncelli, E Webb, R Gueorguieva, DC D’Souza, NN Boutros, L Trevisan and DS Charney (2003b) Altered NMDA glutamate receptor antagonist response in recovering ethanol dependent patients.Neuropsychopharmacol. 28, 2020–2028.Google Scholar
  106. Krystal JH, IL Petrakis, L Trevisan and DC D’Souza (2003c) NMDA receptor antagonism and the ethanol intoxication signal: from alcoholism risk to pharmacotherapy.Ann. NY Acad. Sci 1003, 176–184.PubMedCrossRefGoogle Scholar
  107. Kurs R, H Farkas and M Ritsner (2005) Quality of life and temperament factors in schizophrenia: comparative study of patients, their siblings and controls.Quality Life Res. 14, 433–440.CrossRefGoogle Scholar
  108. Lambert M, C Haasen, R Mass and M Krausz (1997) [Consumption patterns and motivation for use of addictive drugs in schizophrenic patients].Psychiatric Praxis 24, 185–189.Google Scholar
  109. Lamelle M, A Abi-Dargham, CH van Dyck, R Gil, CD D’Souza, J Erdos, E McCance, W Rosenblatt, C Fingado, SS Zoghbi, RM Baldwin, JP Seibyl, JH Krystal, DS Charney and RB Innis (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects.Proc. Natl. Acad. Sci USA 93, 9235–9240.CrossRefGoogle Scholar
  110. Lamelle M, A Abi-Dargham, R Gil, L Kegeles and R Innis (1999) Increased dopamine transmission in schizophrenia: relationship to illness phases.Biol. Psychiatry 46, 56–72.CrossRefGoogle Scholar
  111. Layne C and LT Wallace (1982) Impaired preferences for praise in schizophrenic adolescents.J. Clin. Psychology 38, 51–55.CrossRefGoogle Scholar
  112. Leonard S, C Breese, C Adams, K Benhammou, J Gault, K Stevens, M Lee, L Adler, A Olincy, R Ross and R Freedman (2000) Smoking and schizophrenia: abnormal nicotinic receptor expression.Eur. J. Pharmacol 393, 237–242.PubMedCrossRefGoogle Scholar
  113. Lyons MJ, JL Bar, WS Kremen, R Toomey, SA Eisen, J Goldberg, SV Faraone and M Tsuang (2002) Nicotine and familial vulnerability to schizophrenia: a discordant twin study.J. Abnormal PsychoL 111, 687–693.CrossRefGoogle Scholar
  114. Lysaker P, M Bell, J Beam-Goulet and R Milstein (1994) Relationship of positive and negative symptoms to cocaine abuse in schizophrenia.J. Nerv. Ment. Dis. 182, 109–112.PubMedCrossRefGoogle Scholar
  115. Martin-Solch C, S Magyar, G Kunig, J Missimer, W Schultz and KL Leenders (2001) Changes in brain activation associated with reward processing in smokers and nonsmokers. A positron emission tomography study.Exp. Brain Res. 139, 278–286.PubMedCrossRefGoogle Scholar
  116. Martinez D, A Broft, RW Foltin, M Slifstein, DR Hwang, Y Huang, A Perez, WG Frankle, T Cooper, HD Kleber, MW Fischman and M Laraelle (2004) Cocaine dependence and D2 receptor availability in the functional subdivisions of the striatum: relationship with cocaine-seeking behavior.Neuropsychopharmacol. 29, 1190–1202.CrossRefGoogle Scholar
  117. Martinez D, R Gil, M Slifstein, D-R Hwang, Y Huang, A Perez, L Kegeles, S Evans, JH Krystal and M Laraelle (2005) Alcohol dependence is associated with blunting of dopamine transmission in the ventral striatum.Biol. Psychiatry. E-publication ahead of press.Google Scholar
  118. McReadie RG and SCS Group (2002) Use of drags, alcohol, and tobacco by people with schizophrenia: case-control study.Brit. J. Psychiatry 181, 321–325.CrossRefGoogle Scholar
  119. Meador-Woodruff JH and DJ Healy (2000) Glutamate receptor expression in schizophrenic brain.Brain Res. Brain Res. Rev. 31, 288–294.PubMedCrossRefGoogle Scholar
  120. Melendez RI, ZA Rodd-Henricks, EA Engleman, TK Li, WJ McBride and JM Murphy (2002) Microdialysis of dopamine in the nucleus accumbens of alcohol-preferring (P) rats during anticipation and opérant self-administration of ethanol.Alcoholism: Clin. Exp. Res. 26, 318–325.Google Scholar
  121. Merikangas KR and S Avenevoli (2000) Implications of genetic epidemiology for the prevention of substance use disorders.Addict. Behav. 25, 807–820.PubMedCrossRefGoogle Scholar
  122. Mexal S, M Frank, R Berger, CE Adams, RG Ross, R Freedman and S Leonard (2005) Differential modulation of gene expression in the NMDA postsynaptic density of schizophrenic and control smokers.Brain Res. Mol. Brain Res. 139, 317–332.PubMedCrossRefGoogle Scholar
  123. Mueser KT, PR Yarnold, DF Levinson, H Singh, AS Bellack, K Kee, RL Morrison and KG Yadalam (1990) Prevalence of substance abuse in schizophrenia: demographic and clinical correlates.Schizophr. Bull. 16, 31–56.PubMedGoogle Scholar
  124. Mueser KT, P Nishith, JI Tracy, J DeGirolamo and M Molinaro (1995) Expectations and motives for substance use in schizophrenia.Schizophr. Bull. 21, 367–378.PubMedGoogle Scholar
  125. Mueser KT, RE Drake, TH Ackerson, AI Alterman, KM Miles and DL Noordsy (1997) Antisocial personality disorder, conduct disorder, and substance abuse in schizophrenia.J. Abnormal Psychol 106, 473–477.CrossRefGoogle Scholar
  126. Mueser KT, SD Rosenberg, RE Drake, KM Miles, G Wolford, R Vidaver and K Carrieri (1999) Conduct disorder, antisocial personality disorder and substance use disorders in schizophrenia and major affective disorders.J. Studies Alcohol 60, 278–284.Google Scholar
  127. Mueser KT, SD Rosenberg, LA Goodman and SL Trumbetta (2002) Trauma, PTSD, and the course of severe mental illness: an interactive model.Schizophr. Res. 53, 123–143.PubMedCrossRefGoogle Scholar
  128. Noordsy DL, RE Drake, JC Biesanz and GJ McHugo (1994) Family history of alcoholism in schizophrenia.J. Nerv. Ment. Dis. 182, 651–655.PubMedGoogle Scholar
  129. Noordsy DL and AI Green (2003) Pharmacotherapy for schizophrenia and co-occurring substance use disorders.Curr. Psychiatry Rep. 5, 340–346.PubMedCrossRefGoogle Scholar
  130. Nurnberger JIJ, R Wiegand, K Bucholz, S O’Connor, ET Meyer, T Reich, J Rice, M Schuckit, L King, T Petti, L Bierut, AL Hinrichs, S Kuperman, V Hesselbrock and B Porjesz (2004) A family study of alcohol dependence: coag- gregation of multiple disorders in relatives of alcohol-dependent probands.Arch. Gen. Psychiatry 61, 1246–1256.PubMedCrossRefGoogle Scholar
  131. O’Brien CP, DS Charney, L Lewis, JW Cornish, RM Post, GE Woody, JK Zubieta, JC Anthony, JD Blaine, CL Bowden, JR Calabrese, K Carroll, T Kosten, B Rounsaville, AR Childress, DW Oslin, HM Pettinati, MA Davis, R Demartino, RE Drake, MF Fleming, L Fricks, AH Glassman, FR Levin, EV Nunes, RL Johnson, C Jordan, RC Kessler, SK Laden, DA Regier, JAJ Renner, RK Ries, T Sklar-Blake and C Weisner (2004) Priority actions to improve the care of persons with co-occurring substance abuse and other mental disorders: a call to action.Biol. Psychiatry 56, 703–713.PubMedCrossRefGoogle Scholar
  132. O’Donnell P and AA Grace (1995) Synaptic interactions among excitatory afferents to nucleus accumbens neurons: hippocampal gating of prefrontal cortical input.J. Neurosci. 15, 3622–3639.PubMedGoogle Scholar
  133. O’Donnell P and AA Grace (1998) Phencyclidine interferes with the hippocampal gating of nucleus accumbens neuronal activityin vivo.Neuroscience 87, 823–830.PubMedCrossRefGoogle Scholar
  134. Petrakis IL, D Limoncelli, R Gueorguieva, P Jatlow, NN Boutros, L Trevisan, J Gelernter and JH Krystal (2004a) Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism.Am. J. Psychiatry 161, 1776–1782.PubMedCrossRefGoogle Scholar
  135. Petrakis IL, S O’Malley, B Rounsaville, J Poling, C McHughStrong and JH Krystal (2004b) Naltrexone augmentation of neuroleptic in alcohol-abusing schizophrenic patients.Psychopharmacology 111, 291–297.CrossRefGoogle Scholar
  136. Petry NM (2002) Discounting of delayed rewards in substance abusers: relationship to antisocial personality disorder.Psychopharmacology 162, 425–432.PubMedCrossRefGoogle Scholar
  137. Petry NM, KN Kirby and HR Kranzler (2002) Effects of gender and family history of alcohol dependence on a behavioral task of impulsivity in healthy subjects.J. Studies Alcohol 63, 83–90.Google Scholar
  138. Pierri JN, AS Chaudry, TU Woo and DA Lewis (1999) Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects.Am. J. Psychiatry 156, 1709–1719.PubMedGoogle Scholar
  139. Pilowsky LS, RA Bressan, JM Stone, K Erlandsson, RS Mulligan, JH Krystal and PJ Ell (2006) Firstin vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients.Mol. Psychiatry 11, 118–119.PubMedCrossRefGoogle Scholar
  140. Pollock VE (1992) Meta-analysis of subjective sensitivity to alcohol in sons of alcoholics.Am. J. Psychiatry 149, 1534- 1538.PubMedGoogle Scholar
  141. Regier DA, ME Farmer, DS Rae, BZ Locke, SJ Keith, LL Judd and FK Goodwin (1990) Comorbidity of mental disorders with alcohol and other drag abuse. Results from the Epidemiologie Catchment Area (EGA) Study.JAMA 264, 2511–2518.PubMedCrossRefGoogle Scholar
  142. Reith J, C Benkelfat, A Sherwin, Y Yasuhara, H Kuwabara, F Andermann, S Bachneff, P Gumming, M Diksic, SE Dyveet al. (1994) Elevated dopa decarboxylase activity in living brain of patients with psychosis.Proc. Natl. Acad. Sci USA. 91, 11651–11654.PubMedCrossRefGoogle Scholar
  143. Resnick SG, GR Bond and KT Mueser (2003) Trauma and posttraumatic stress disorder in people with schizophrenia.J. Abnormal Psychol. 112, 415–423.CrossRefGoogle Scholar
  144. Ritter LM, JH Meador-Woodruff and GW Dalack (2004) Neurocognitive measures of prefrontal cortical dysfunction in schizophrenia.Schizophr Res. 68, 65–73.PubMedCrossRefGoogle Scholar
  145. Robbins TW and BJ Everitt (1996) Neurobehavioural mechanisms of reward and motivation.Curr. Opin. Neurobiol. 6, 228–236.PubMedCrossRefGoogle Scholar
  146. Rogers RD, BJ Everitt, A Baldacchino, AJ Blackshaw, R Swainson, K Wynne, NB Baker, J Hunter, T Carthy, E Booker, M London, JF Deakin, BJ Sahakian and TW Robbins (1999) Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence for monoaminergic mechanisms.Neuropsychopharmacol. 20, 322–339.CrossRefGoogle Scholar
  147. Rolls ET (1999)The Brain and Emotion (Oxford University Press: Oxford).Google Scholar
  148. Sacco KA, A Termine, A Seyal, MM Dudas, JC Vessicchio, S Krishnan-Sarin, PI Jatlow, BE Wexler and T George, (2005) Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms.Arch. Gen. Psychiatry 62, 649–659.PubMedCrossRefGoogle Scholar
  149. Scheller-Gilkey G, K Moynes, I Cooper, C Kant and AH Miller (2004) Early life stress and PTSD symptoms in patients with comorbid schizophrenia and substance abuse.Schizophr. Res. 69, 167–174.PubMedCrossRefGoogle Scholar
  150. Schneier FR and SG Siris (1987) A review of psychoactive substance use and abuse in schizophrenia. Patterns of drug choice.J. Nerv. Ment. Dis. 175, 641–652.PubMedCrossRefGoogle Scholar
  151. Schuckit MA (1994) Low level of response to alcohol as a predictor of future alcoholism.Am. J. Psychiatry 151, 184- 189.PubMedGoogle Scholar
  152. Schuckit MA and TL Smith (1996) An 8-year follow-up of 450 sons of alcoholic and control subjects.Arch. Gen. Psychiatry 53, 202–210.PubMedGoogle Scholar
  153. Schultz W (1998) Predictive reward signal of dopamine neurons.J. Neurophysiol. 80, 1–27.PubMedGoogle Scholar
  154. Seibyl JP, SL Satel, D Anthony, SM Southwick, JH Krystal and DS Charney (1993) Effects of cocaine on hospital course in schizophrenia.J. Nerv. Ment. Dis. 181, 31–37.PubMedCrossRefGoogle Scholar
  155. Seidman LJ, NL Talbot, AG Kalinowski, RW McCarley, SV Faraone, WS Kremen, JR. Pepple and MT Tsuang (1991) Neuropsychological probes of fronto-limbic system dys- function in schizophrenia, olfactory identification and Wisconsin Card Sorting performance.Schizophr. Res. 6, 55–65.PubMedCrossRefGoogle Scholar
  156. Shurman B, WP Horan and KH Neuchterlein (2005) Schizophrenia patients demonstrate a distinctive pattern of decision-making impairment on the Iowa Gambling Task.Schizophr. Res. 72, 215–224.PubMedCrossRefGoogle Scholar
  157. Sibitz I, H Katschnig, R Goessler, A Unger and M Amering (2005) Pharmacophilia and pharmacophobia: determinants of patients’ attitudes towards antipsychotic medication.Pharmacopsychiatry 3, 107–112.CrossRefGoogle Scholar
  158. Spring B, R Pingitore and DE McChargue (2003) Reward value of cigarette smoking for comparably heavy smoking schizophrenic, depressed, and nonpatient smokers.Am. J. Psychiatry 160, 316–322.PubMedCrossRefGoogle Scholar
  159. Swartz MS, HR Wagner, JW Swanson, TS Stroup, JP McEvoy, JM Canive, D.D. M, F Reimherr, M McGee, A Khan, R Van Dorn, RA Rosenheck and JA Lieberman (2006) Substance use in persons with schizophrenia: baseline prevalence and correlates from the NIMH CATIE study.J. Nerv. Ment. Dis. 1949 164–172.Google Scholar
  160. Tobler PN, CD Fiorillo and W Schultz (2005) Adaptive coding of reward value by dopamine neurons.Science 307, 1642–1645.PubMedCrossRefGoogle Scholar
  161. Ullman L and RP Forsythe (1959) Responses by normal and schizophrenic subjects under positive and negative examiner reinforcement in a probability learning situation.Am. Psychologist 14, 407–408.Google Scholar
  162. Vastag B (2004) Brain sabotages sobriety, right on cue: Pavlov’s progeny provide pictures of alcoholism.JAMA 291, 1053- 1055.PubMedCrossRefGoogle Scholar
  163. Verdoux H, M Mury, G Besancon and M Bourgeois (1996) [Comparative study of substance dependence comorbid- ity in bipolar, schizophrenic and schizoaffective disorders].Encephale 22, 95–101.PubMedGoogle Scholar
  164. Volkow ND, L Chang, GJ Wang, JS Fowler, YS Ding, M Sedler, J Logan, D Franceschi, J Gatley, R Hitzemann, A Gifford, C Wong and N Pappas (2001) Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex.Am. J. Psychiatry 158, 2015–2021.PubMedCrossRefGoogle Scholar
  165. Volkow ND, GJ Wang, H Begleiter, R Hitzemann, N Pappas, G Burr, K Pascani, C Wong, JS Fowler and AP Wolf (1995) Regional brain metabolic response to lorazepam in subjects at risk for alcoholism.Alcoholism, Clin. Exp. Res. 19, 510–516.CrossRefGoogle Scholar
  166. Volkow ND, GJ Wang, JS Fowler, J Logan, R Hitzemann, YS Ding, N Pappas, C Shea and K Piscani (1996) Decreases in dopamine receptors but not in dopamine transporters in alcoholics.Alcoholism, Clin. Exp. Res. 20, 1594–1598.Google Scholar
  167. Wilder KE, DR Weinberger and TE Goldberg (1998) Operant conditioning and the orbitofrontal cortex in schizophrenia patients: unexpected evidence for intact functioning.Schizophr. Res. 30, 169–174.PubMedCrossRefGoogle Scholar
  168. Xie H, GJ McHugo, BS Helmstetter and RE Drake (2005) Three-year recovery outcomes for long-term patients with co-occurring schizophrenic and substance use disorders.Schizophr. Res. 75, 337–348.PubMedCrossRefGoogle Scholar
  169. Zuckerman M (1979)Sensation Seeking: Beyond the Optimal Level of Arousal (Lawrence Erlbaum Press:Mahwah, NJ).Google Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  • John H. Krystal
    • 1
    • 2
    • 3
    • 4
  • D. Cyril D’Souza
    • 1
    • 2
    • 3
    • 4
  • JÜrgen Gallinat
    • 5
  • Naomi Driesen
    • 1
    • 2
  • Anissa Abi-Dargham
    • 6
  • Ismene Petrakis
    • 1
    • 2
    • 3
  • Andreas Heinz
    • 5
  • Godfrey Pearlson
    • 1
    • 7
  1. 1.Department of PsychiatryYale University School of MedicineNew HavenUSA
  2. 2.Schizophrenia Biological Research Center (116-A)VA Connecticut Healthcare SystemWest HavenUSA
  3. 3.Alcohol Research Center (116-A)VA Connecticut Healthcare SystemWest HavenUSA
  4. 4.Abraham Ribicoff Research FacilitiesConnecticut Mental Health CenterNew HavenUSA
  5. 5.Department of PsychiatryCharité University MedicineCampus Mitte, BerlinGermany
  6. 6.New York State Psychiatric Institute, Department of PsychiatryColumbia UniversityNew YorkUSA
  7. 7.Olin Neuropsychiatry Research CenterInstitute of LivingHartfordUSA

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