The Link Between Psychotic Disorders and Substance Use

Psychotic disorders are a group of syndromes characterized by positive symptoms, including hallucinations, delusions, and thought disorder; and negative symptoms, including mood symptoms, social withdrawal, and reduced motivation. Cognitive deficits also appear with psychotic disorders. Psychotic disorders rank 22nd in the World Health Organization's list of worldwide causes of disability.¹ This ranking is adjusted for the relatively low lifetime prevalence rate for psychosis; the perceived burden of the disease on those affected with psychotic disorders, as well as their relatives and caregivers, is much higher.² Some symptoms are present, albeit in an attenuated form, prior to the onset of a diagnosable disorder. Features of psychotic disorders are detectable in the general population and are referred to as schizotypal traits, representing a normally distributed trait of risk for psychosis.

A recent large study of patients in their first episode of psychosis found a 74% lifetime prevalence of a substance use disorder, with 62% of the sample presenting at baseline with current substance use.³ Alcohol, nicotine, and cannabis are the predominant substances abused by patients with psychotic disorders.⁴ A US epidemiology study reported the risk for substance use as 4.6 fold higher in patients with schizophrenia compared with the general population.⁵ Even in Sweden, where there are tight restrictions on the sale of alcohol, patient consumption far exceeds rates reported in the general population.⁶

Relationship with onset
There has been much discussion about the relationship between recreational drug use, psychotic symptoms, and psychotic disorders, particularly with the increasing tolerance for drugs such as cannabis (by society and government). Substance use patterns seem to establish themselves before the onset of psychotic disorders; in a significant proportion of individuals, this may be as little as a month before the first signs of illness.⁷ The close temporal proximity of substance use to emerging signs or symptoms of psychotic illness may be an indication for the causal relationship between psychotic disorders and substance use, although this is open for debate.⁸

It is difficult to determine whether those prone to psychosis are self-medicating initial symptoms, or whether they are drawn to substance use by factors unrelated to illness, such as personality traits. In addition, patterns of substance use before onset of illness may be indicative of other risk factors that are associated with lifestyle changes linked to the beginning of deterioration into psychosis and detrimental factors directly related to increased drug use.

There are 2 hypotheses regarding the onset of psychotic disorders that are of interest to researchers and clinicians:

• Drug use triggers psychotic symptoms in those individuals who have an underlying predisposition to psychotic disorders.
• Exposure to recreational drug use is sufficient in itself to lead to these symptoms independent of underlying predisposition.

The NEMESIS project tested these hypotheses in regards to cannabis use. Van Os and colleagues⁹ reported that those who displayed a vulnerability to psychotic disorders at baseline were more likely to experience isolated psychotic symptoms after cannabis use. In addition, use of cannabis alone led to the increased likelihood of isolated psychotic symptoms reported at follow-up. Furthermore, one study found higher reports of psychotic-like and psychopathologic experiences from cannabis use (both during the immediate high and during following use) in those individuals with an elevated propensity toward psychosis.¹⁰ These data suggest that cannabis use may trigger an underlying vulnerability to isolated symptoms through an unknown mechanism. There is limited evidence that perhaps in high doses,¹¹ cannabis in the absence of any vulnerability can lead to isolated psychotic symptoms. However, isolated incidences of psychotic symptoms are not sufficient for a diagnosis of any psychotic disorder, and therefore, there are additional factors that lead to the onset of a psychotic disorder.

The most robust body of evidence for the relationship between the onset of psychotic disorders and drug use comes from the Swedish conscript studies.^12,13 Baseline drug use information was taken at intake to the army for these studies. The authors found that cannabis use, and to a lesser extent amphetamine use, predicted onset of psychotic disorder later in adulthood. The explanatory variable was age at use, with younger age predicting psychotic disorders. This relationship did not exist for other drugs used, such as cocaine. A more recent cohort study in New Zealand confirmed the relationship between cannabis use and the onset of psychotic disorders.¹⁴ This study demonstrated that younger age of first cannabis use predicted younger age of psychotic disorder onset in individuals with the Val/Val genotype for COMT on the Val158Met polymorphism (a gene that codes for the activity level of an enzyme involved in the breakdown of dopamine).

Course of psychosis and substance useThere is conflicting evidence of the effects of substance use on age at psychotic disorder onset. Some studies have found that substance use leads to a younger age at symptom onset and/or diagnosis,^7,15,16 while other studies have found no association.¹⁷ Some investigators have suggested that patients who have an onset related to drug use have a distinct subtype of psychotic disorder. Drug-induced psychosis is still considered diagnostically distinct from psychotic disorders, since in the former, symptoms abate when substance use is discontinued, while symptoms in the latter persist. However, as previously noted, those who experience isolated psychotic symptoms in relation to drug use may have an underlying predisposition to psychosis.

Substance use during the course of psychotic illness may have implications for relapse and may interfere with treatment. Thus, finding predictors of continued use following an initial psychotic episode would identify those patients who may require further interventions and/or close monitoring. The most consistently reported predictors of continued use are young age and male sex.^15,16,18 Previous studies have reported that young men are significantly more likely to use substances or to use more than one substance; this helps explain why male sex proves to be a significant predictor of continued use.⁶ Compared with patients who have just substance use disorder, patients with psychotic disorder and substance dependence are more likely to be using substances after 7 years.¹⁹ This further suggests that those with more severe substance use problems should be identified for targeted interventions concerned with reducing substance use.

However, there is some suggestion that substance use decreases following treatment initiation. Three studies have examined the course of substance use in the early phases of psychotic disorders. Two have shown a marked reduction in substance use during early treatment, compared with that in the pretreatment period.^18,20 A third study found that 1 in 5 patients with psychotic disorders stopped using substances 15 months after their first episode.²¹ Those patients who continued use did not increase their baseline use, and very few patients developed substance use behavior after treatment began. Taken together, these studies offer some room for optimism. It seems that a significant proportion of patients with psychotic disorders decrease or discontinue substance use once treatment has been initiated, while those who continue use do not increase their intake.

Exacerbation of symptoms and relapse
The relationship between substance use and symptoms in psychotic disorders is varied. Some studies report a relationship with increased symptoms,^22-24 while others do not.^25-27 However, there appears to be a relationship in those with psychotic disorders between substance use and increased hospitalization and remission,^3,26,28-31 although not all studies report these findings.^32,33 The relationship between remission in patients with psychotic disorders and comorbid substance use can in part be explained by reports of reduced adherence to medication regimens and engagement in services.^3,7,26 One study reported that relapse occurs even when medication adherence has been fully documented (ie, it is not an issue),³⁴ suggesting the possibility of an interaction between the substances used and antipsychotic medication.

Treatment approaches for substance use
Support for the possibility of an interaction between substances used by patients with psychotic disorders and antipsychotics comes from reports that those with substance use problems have a poorer response to treatment.^4,6 There is an overlap in the neurobiologic networks involved in the development and maintenance of substance use and psychotic disorders.³⁵ Taken together, these studies suggest that those with comorbid substance use and psychotic disorder may require additional treatment, either in the form of targeted psychological or additional pharmacologic interventions, to address symptoms associated with substance use. There is emerging evidence that this integrated treatment approach is effective in patients with a dual diagnosis.³⁶ However, psychological interventions are only effective at targeting symptoms that the patient wishes to change.

There is no evidence that typical antipsychotics are particularly effective in treating patients with psychotic disorders and substance use problems; there is even some suggestion that haloperidol use increases tobacco smoking.³⁷ There is some evidence that the atypical antipsychotic clozapine may reduce substance use in patients with psychotic disorders.^38,39 Alcohol, nicotine, and cannabis use are reported to decrease in response to clozapine treatment; there are some indications that clozapine reduces cocaine cravings and use.⁴⁰

Clozapine has also been reported to be more effective in reducing substance use as compared with risperidone, and it has been reported to be better tolerated, leading to continuation of treatment over 12 months.⁴¹ In addition, patients with comorbid substance use problems and psychotic disorder respond equally well to clozapine as those who do not have substance use problems.⁴² It has been suggested that clozapine reduces substance use through its effects on the dopamine-dependent reward pathways,⁴³ but this mechanism has yet to be formally tested.

A large-scale prospective randomized controlled trial has not been carried out to test the reduction in substance use in a large sample of patients with psychotic disorders treated with clozapine. Such a trial is needed to substantiate results from smaller studies.

Other atypical antipsychotics have proved to be of interest in treating substance use in patients with psychotic disorders. Risperidone has been reported to reduce cocaine craving and relapse.^44,45 Olanzapine has also been reported to lead to small reductions in substance use and decreased craving for a variety of substances in those with psychotic disorders.^46-48 However, systematic prospective randomized controlled trials have yet to test the efficacy of these drugs in reducing substance use in patients with psychotic disorders.

Conclusions
There appears to be evidence of substance use (at least cannabis use) as a component cause for psychotic disorders. However, it is still unclear whether substance use operates as a causal factor in the absence of underlying biologic vulnerability to psychosis and whether the expression of isolated psychotic symptoms is directly related to clinical psychotic disorders. The evidence for the causal relationship between substance use and psychotic disorders is primarily based on epidemiologic studies; further clinical studies are needed to determine how substance use operates as a risk factor for psychotic disorders. It is possible that this evidence will emerge from the growing numbers of early intervention services worldwide.

According to a recent review, published studies examining the effect of substance use on the course of schizophrenia are drawn from North America, Australia, and a select number of European countries.⁶ Therefore, many countries have not contributed to the literature. This is particularly true for developing countries, where the demographic of substance users is likely to be different.

There is a need for more systematic research in this area. In particular, there is a need for systematic large-scale research to examine the causal role of substance use in altering the course of psychotic disorders, where current research is highly conflicting. Focusing on the reasons that patients with psychotic disorders abuse substances (eg, to relieve affective flattening and negative symptoms⁷) may produce information on unmet needs that can be targeted by specifically developed therapies in the future. In addition, the pharmacologic interventions that show promise in treating substance use in those patients with psychotic disorders need to be investigated more systematically to better understand their benefits and their underlying mechanisms.

Dr Barkus is a research fellow in the Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK. She reports no conflicts of interest concerning the subject matter of this article.

References:

References1. World Health Organization. The double burden: emerging epidemics and persistent problems. Available at: http://www.who.int/whr/1999/en/whr99_ch2_en.pdf. Accessed November 22, 2006.
2. Ustun TB, Rehm J, Chatterji S, et al. Multiple-informant ranking of the disabling effects of different health conditions in 14 countries. WHO/NIH Joint Project CAR Study Group. Lancet. 1999;354:111-115.
3. Lambert M, Conus P, Lubman DI, et al. The impact of substance use disorders on clinical outcome in 643 patients with first-episode psychosis. Acta Psychiatr Scand. 2005;112:141-148.
4. Kavanagh DJ, Waghorn G, Jenner L, et al. Demographic and clinical correlates of comorbid substance use disorders in psychosis: multivariate analyses from an epidemiologic sample. Schizophr Res. 2004;66:115-124.
5. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) study. JAMA. 1990;264:2511-2518.
6. Cantor-Graae E, Nordstrom LG, McNeil TF. Substance abuse in schizophrenia: a review of the literature and a study of correlates in Sweden. Schizophr Res. 2001;48:69-82.
7. Bühler B, Hambrecht M, LÅ¡ffler W, et al. 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. 2002;54:243-251.
8. Smith J, Hucker S. Schizophrenia and substance abuse. Br J Psychiatry. 1994;165:13-21.
9. van Os J, Bak M, Hanssen M, et al. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol. 2002;156:319-327.
10. Barkus EJ, Stirling J, Hopkins RS, Lewis S. Cannabis-induced psychosis-like experiences are associated with high schizotypy. Psychopathology. 2006;39:175-178.
11. Thirthalli J, Benegal V. Psychosis among substances users. Curr Opin Psychiatry. 2006;19:239-245.
12. Andreasson S, Allebeck P, Engstršm A, Rydberg U. Cannabis and schizophrenia: a longitudinal study of Swedish conscripts. Lancet. 1987;2:1483-1486.
13. Zammit S, Allebeck P, Andreasson S, et al. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ. 2002;325:1199.
14. Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry. 2005;57:1117-1127.
15. Cantwell R, Brewin J, Glazebrook C, et al. Prevalence of substance misuse in first-episode psychosis. Br J Psychiatry. 1999;174:150-153.
16. Van Mastrigt S, Addington J, Addington D. Substance misuse at presentation to an early psychosis program. Soc Psychiatry Psychiatr Epidemiol. 2004;39:69-72.
17. Sevy S, Robinson DG, Holloway S, et al. Correlates of substance misuse in patients with first-episode schizophrenia and schizoaffective disorder. Acta Psychiatr Scand. 2001;104:367-374.
18. Addington J, Addington D. Impact of an early psychosis program on substance use. Psychiatr Rehabil J. 2001;25:60-67.
19. Bartels SJ, Drake RE, Wallach MA. Long-term course of substance use disorders among patients with severe mental illness. Psychiatr Serv. 1995;46:248-251.
20. Sorbara F, Liraud F, Assens F, et al. Substance use and the course of early psychosis: a 2-year follow-up of first admitted subjects. Eur Psychiatry. 2003;18:133-136.
21. Wade D, Harrigan S, Edwards J, et al. Course of substance misuse and daily tobacco use in first-episode psychosis. Schizophr Res. 2006;81:145-150.
22. Haywood TW, Kravitz HM, Grossman LS, et al. Predicting the "revolving door" phenomenon among patients with schizophrenia, schizoaffective, and affective disorders. Am J Psychiatry. 1995;152;856-861.
23. Serper MR, Alpert M, Richardson NA, et al. Clinical effects of recent cocaine use on patients with acute schizophrenia. Am J Psychiatry. 1995;152:1464-1469.
24. Soyka M, Albus M, Immler B, et al. Psychopathology in dual diagnosis and non-addicted schizophrenics: are there differences? Eur Arch Psychiatry Clin Neurosci. 2001;251:232-8.
25. Wade D, Harrigan S, Whelan G, et al. The impact of substance abuse on recovery and relapse rates and service use in first episode psychosis. Schizophr Res. 2004;67(suppl 1):221.
26. Møller T, Linaker OM. Symptoms and lifetime treatment experiences in psychotic patients with and without substance abuse. Nord J Psychiatry. 2004;58:237-242.
27. Barnes TR, Mutsatsa SH, Hutton SB, et al. Comorbid substance use and age at onset of schizophrenia. Br J Psychiatry. 2006;188:237-242.
28. Cleghorn JM, Kaplan RD, Szechtman B, et al. Substance abuse and schizophrenia: effect on symptoms but not on neurocognitive function. J Clin Psychiatry. 1991;52:26-30.
29. Drake RE, Osher FC, Wallach MA. Alcohol use and abuse in schizophrenia: a prospective community study. J Nerv Ment Dis. 1989;177:408-414.
30. Gerding LB, Labbate LA, Measom MO, et al. Alcohol dependence and hospitalization in schizophrenia. Schizophr Res. 1999;38:71-75.
31. LeDuc PA, Mittleman G. Schizophrenia and psychostimulant abuse: a review and re-analysis of clinical evidence. Psychopharmacology (Berl). 1995;121:407-427.
32. Mueser KT, Yarnold PR, Levinson DF, et al. Prevalence of substance abuse in schizophrenia: demographic and clinical correlates. Schizophr Bull. 1990;16:31-56.
33. Mueser KT, Yarnold PR, Rosenberg SD, et al. Substance use disorder in hospitalized severely mentally ill psychiatric patients: prevalence, correlates, and subgroups. Schizophr Bull. 2000;26:179-192.
34. Gupta S, Hendricks S, Kenkel AM, et al. Relapse in schizophrenia: is there a relationship to substance abuse. Schizophr Res. 1996;20:153-156.
35. Laviolette SR, Grace AA. The roles of cannabinoid and dopamine receptor systems in neural emotional learning circuits: implications for schizophrenia and addiction. Cell Mol Life Sci. 2006;63:1597-1613.
36. Drake RE, Essock SM, Shaner A, et al. Implementing dual diagnosis services for clients with severe mental illness. Psychiatr Serv. 2001;52:469-476.
37. McEvoy JP, Freudenreich O, Levin ED, Rose JE. Haloperidol increases smoking in patients with schizophrenia. Psychopharmacology (Berl). 1995;119:124-126.
38. Zimmet SV, Strous RD, Burgess ES, et al. Effects of clozapine on substance use in patients with schizophrenia and schizoaffective disorder: a retrospective survey. J Clin Psychopharmacol. 2000;20:94-98.
39. Drake RE, Xie H, McHugo GJ, Green AI. The effects of clozapine on alcohol and drug use disorders among patients with schizophrenia. Schizophr Bull. 2000;26:441-449.
40. Yovell Y, Opler LA. Clozapine reverses cocaine craving in a treatment-resistant mentally ill chemical abuser: a case report and a hypothesis. J Nerv Ment Dis. 1994;182:591-592.
41. Green AI, Burgess ES, Dawson R, et al. Alcohol and cannabis use in schizophrenia: effects of clozapine vs. risperidone. Schizophr Res. 2003;60:81-85.
42. Buckley P, Thompson P, Way L, Meltzer HY. Substance abuse among patients with treatment-resistant schizophrenia: characteristics and implications for clozapine therapy. Am J Psychiatry. 1994;151:385-389.
43. Green AI, Zimmet SV, Strous RD, Schildkraut JJ. Clozapine for comorbid substance use disorder and schizophrenia: do patients with schizophrenia have a reward deficiency syndrome that can be ameliorated by clozapine? Harv Rev Psychiatry. 1999;6:287-296.
44. Smelson DA, Losonczy MF, Davis CW, et al. Risperidone decreases craving and relapses in individuals with schizophrenia and cocaine dependence. Can J Psychiatry. 2002;47:671-675.
45. Tsuang JW, Eckman T, Marder S, Tucker D. Can risperidone reduce cocaine use in substance abusing schizophrenic patients? J Clin Psychopharmacol. 2002;22:629-630.
46. Conley RR, Kelly DL, Gale EA. Olanzapine response in treatment-refractory schizophrenic patients with a history of substance abuse. Schizophr Res. 1998;33:95-101.
47. Smelson DA, Ziedonis DM, Losonczy MF, et al. A double blind study comparing olanzapine to haloperidol for reducing pre-elicited cravings in individuals with schizophrenia and cocaine dependence. Schizophr Res. 2003;60 (suppl 11):303.
48. Tsuang J, Marder SR, Han A, Hsieh W. Olanzapine treatment for patients with schizophrenia and cocaine abuse. J Clin Psychiatry. 2002;63:1180-1181.