Substance Abuse and Schizophrenia:
`Editors' Introduction
`by Thomas R. Kosten and Douglas M. Ziedords
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`Abstract
`
`Most individuals with schizophrenia have problems
`with abuse of substances ranging from licit substances,
`such as nicotine, to Illicit ones, such as cocaine. This
`comorbidity may reflect self-medication, as well as a
`biological susceptibility to both disorders. Twin studies
`have suggested that this biological susceptibility may
`involve genetic factors. Other biological risk factors
`may Involve the medications used to treat schizophre-
`nia, which may produce symptoms that provoke abuse
`of drugs to relieve negative symptoms or may even
`enhance the euphoric response to abused drugs. The
`articles in this issue address several research areas
`related to substance abuse and schizophrenia, includ-
`ing the differential diagnosis of schizophrenia and
`organic disorders induced by substance abuse and the
`impact of substance abuse on the course of early schiz-
`ophrenia. The management of substance-abusing
`schizophrenia patients requires a careful balance of
`phannacotherapy and psychotherapies, and atypical
`antipsychotic agents may be particularly helpful.
`Psychotherapy needs to focus both on the management
`of affect and on the adequate monitoring of drug
`abstinence.
`Schizophrenia Bulletin, 23<2):181-186,1997.
`
`Several recent studies have demonstrated that up to 50
`percent of individuals with schizophrenia have either
`alcohol or illicit drug dependence, and about 70 percent or
`more are nicotine dependent (Andreasson et al. 1987;
`Brady et al. 1990; Dixon et al. 1991; Shaner et al. 1993;
`Ziedonis et al. 1994). This high rate of comorbidity with
`substance abuse reflects the influence of risk factors rang-
`ing from genetic vulnerability to prominent negative
`symptoms to medication side effects to psychosocial fac-
`tors, such as low socioeconomic status, living with other
`users, and chronic life stressors. The substance abuse may
`also exacerbate schizophrenia and precipitate psychotic
`
`episodes. Although a self-medication hypothesis has sug-
`gested that the use of drugs may acutely ameliorate some
`negative and positive symptoms of schizophrenia, the
`chronic effect of these abused drugs is detrimental to the
`psychological well-being of these patients (Khantzian
`1985). This detrimental effect may simply be the conse-
`quent noncompliance with antipsychotic agents, but it can
`also reflect the direct neurochemical effects of stimulants,
`hallucinogens, or alcohol in precipitating psychotic symp-
`toms. Biological susceptibility to both substance abuse
`and schizophrenia may be an important factor in these
`direct neurochemical effects of abused drugs such as alco-
`hol and may be related to a shared genetic predisposition
`for both disorders.
`Genetic factors have been linked to both alcoholism
`and schizophrenia (Rimmer and Jacobsen 1977;
`Gottesman and Shields 1982; Goodwin 1983), but little
`research has assessed the etiological role of genetic fac-
`tors when the disorders occur together. A twin study by
`Kendler (1985) provided some provocative data on this
`comorbidity by addressing two possible roles played by
`genes in this association. First, although Freed (1975)
`focused on the role of certain life stresses being associ-
`ated with both disorders in his review of the literature on
`co-occurring alcoholism and schizophrenia, the data by
`Kendler do not support a strong correlation between the
`environmental precipitants of these two disorders. The
`diagnoses of schizophrenia and alcoholism were uncorre-
`lated in the cotwins of the monozygotic (MZ) index twins,
`indicating that the specific environmental factors of causal
`importance in the two disorders are not related closely.
`Second, in individuals with both disorders, genetic
`factors were not simply important for schizophrenia alone
`or for alcoholism alone. For example, individuals geneti-
`cally predisposed to schizophrenia did not then develop
`
`Reprint requests should be sent to Dr. T.R. Kosten, Yale University
`School of Medicine, VA Connecticut Healthcare System, Psychiatry
`116A, 950 Campbell Ave., West Haven, CT 06516.
`
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`T.R. Kosten and D.M. Ziedonis
`
`alcoholism as self-medication or as a means of coping
`with the anxiety related to their psychotic symptoms.
`Since the age at onset for schizophrenia preceded the
`diagnosis of alcoholism in only about half the twins, with
`no difference between the dizygotic (DZ) and MZ twins, a
`simple self-medication hypothesis of alcoholism for
`schizophrenia symptoms was not plausible for about half
`the patients in this study. (However, see the Khantzian
`(1985) self-medication hypothesis described later.)
`Furthermore, based on these twin studies, individuals pre-
`disposed to alcoholism and abuse of other drugs such as
`hallucinogens were not simply prone to develop schizo-
`phrenia-like symptomatology, such as auditory hallucina-
`tions and persecutory delusions (Victor and Hope 1958).
`Instead, these 34 MZ and 47 DZ twins with diagnoses of
`both alcoholism and schizophrenia had a genetic predis-
`position to both disorders similar to that which causes the
`two to occur alone.
`This final finding indicates a shared genetic predispo-
`sition to both disorders. Since both disorders are most
`likely polygenic in inheritance, they may stem from the
`same abnormalities in several genes, such as those regu-
`lating dopamine or serotonin receptors or metabolism in
`neurons. Future genetic linkage studies should address
`this issue.
`Another potential biological risk factor involves the
`medications that are used to treat schizophrenia. Although
`acute neuroleptics may diminish some of the effects of
`abused drugs, particularly stimulants, the chronic effects
`of neuroleptics seem to enhance these same reinforcing
`properties. Recent studies in rodents have demonstrated
`that chronic treatment with haloperidol increases the rein-
`forcing effects of cocaine (Kosten and Nestler 1994). This
`experimental observation in animals is consistent with
`patient reports about why they abuse cocaine and other
`drugs. Psychotic patients often report substantial euphoria
`from relatively modest dosages of cocaine, even while
`still continuing their neuroleptics. The mechanism of this
`enhanced response is presumably due to upregulation of
`the postsynaptic receptor for dopamine secondary to
`chronic neuroleptic blockade. Other anecdotal human
`work and human experimental studies further suggest that
`acute neuroleptic treatment does not reduce the positive
`euphoric qualities of cocaine, but may in fact only reduce
`the dysphoria and paranoia-inducing aspects of stimulant
`use (Gawin 1986; Sherer et al. 1989). Furthermore, schiz-
`ophrenia patients who abuse stimulants and marijuana fre-
`quently report relief of the negative symptoms of schizo-
`phrenia and amelioration of the dysphoric effects of neu-
`roleptics (Schneier and Sins 1987; Brady et al. 1990;
`Kelly et al. 1992; Albanese et al. 1994; Serper et al.
`1995). Negative symptoms of schizophrenia are not well
`
`relieved by typical neuroleptics. However, the new atypi-
`cal neuroleptics (e.g., clozapine, risperidone) may offer an
`important alternative. The article by Therese Kosten
`(1997, this issue) reports on recent studies with rodents
`that suggest the potential clinical utility of these agents
`for cocaine abusers. Finally, the efficacy of neuroleptics
`may be compromised by induction of their metabolism by
`nicotine in those 70 percent or more of individuals with
`schizophrenia who are nicotine dependent (Pantuck et al.
`1982).
`In summary, a variety of biological interactions may
`occur between neuroleptics and abused drugs. These inter-
`actions may potentiate the effects of abused drugs,
`thereby increasing their reinforcing properties. These
`interactions may also decrease the efficacy of neuroleptics
`directly via metabolic induction or indirectly through lack
`of compliance with neuroleptics. Poor compliance by sub-
`stance-abusing schizophrenia patients commonly precedes
`an exacerbation of their psychosis and subsequent hospi-
`talization.
`When assessing patients with psychotic symptoms
`and substance abuse, an accurate diagnosis is essential. A
`variety of abused substances ranging from marijuana to
`alcohol can induce transient psychotic states that are not
`indicative of an underlying schizophrenic disorder. The
`article by Rosenthal and Miner (1997, this issue) exam-
`ines the important indicators differentiating schizophrenia
`from a drug-induced psychosis, including the types of
`psychotic material elicited from the patient. An important
`correlate of an accurate diagnosis is appropriate use of
`psychiatric treatment resources, including avoiding hospi-
`talization in those patients who can make an adequate
`recovery while being held for 1 to 2 days in the emer-
`gency room. An accurate diagnosis also enables under-
`standing of the longer-term implications for the course of
`substance abuse in individuals appropriately diagnosed
`with schizophrenia.
`Patients with schizophrenia who are being treated in
`mental health settings often have undetected substance
`abuse. Routine urine testing in triage settings and during
`periods of poor clinical response is important (Shaner et
`al. 1993). Important clinical clues of substance abuse
`include legal problems, episodic homelessness, poor treat-
`ment compliance, and recurrent use of the emergency
`room or need for rehospitalization.
`Another important clinical clue to substance abuse is
`cigarette smoking, especially heavy smoking of more than
`25 cigarettes per day. In this journal, Ziedonis and George
`(1997, this issue) review nicotine use and schizophrenia.
`Nicotine is a potent drug that alters psychiatric symptoms
`and medication blood levels, and nicotine use is a gateway
`to other substance abuses.
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`Substance Abuse and Schizophrenia
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`Schizophrenia Bulletin, Vol. 23, No. 2, 1997
`
`The impact of substance abuse on the course of early
`schizophrenia is examined in depth by Kovasznay and
`colleagues (J997, this issue), who critically compare sub-
`stance abusers that have schizophrenia with substance
`abusers who have affective disorders. Affective disorders
`are the major psychiatric comorbidity seen among sub-
`stance abusers, who have rates of lifetime affective disor-
`der ranging from 30 to 60 percent. The rate of schizophre-
`nia in substance abusers is substantially lower and not sig-
`nificantly greater than community rates of schizophrenia,
`which are about 1 percent (Rounsaville et al. 1982; Regier
`et al. 1990). As indicated earlier, however, the 50 percent
`rate of substance abuse in individuals with schizophrenia
`is substantially higher than community rates of substance
`abuse. A recent study demonstrated that, over the lifetime
`course of affective disorders, substance-abusing and
`nonabusing patients tend to have equivalent rates of
`depressive relapses, but the substance abusers recover
`from the depressive relapses more slowly and are less
`readily responsive to treatments (Mueller et al. 1994).
`Ries and Comtois (1997, this issue) carefully demon-
`strates no difference in outcome for those patients with or
`without substance abuse during their first episode of
`depression. In contrast, substance-abusing schizophrenia
`patients have significantly worse 6-month outcomes than
`nonabusing schizophrenia patients. Thus, even in the early
`course of the illness after the first hospitalization, schizo-
`phrenia patients already experience the detrimental effects
`of substance abuse.
`The poor outcome with standard treatments in sub-
`stance-abusing schizophrenia patients may be improved
`by a variety of psychosocial and medication interventions.
`Ziedonis and Trudeau (1997, this issue) report poor moti-
`vation to quit using substances and suggest a dual-diagno-
`sis treatment-matching strategy based on motivational
`level, type of substance, and severity of illness. In addi-
`tion to the use of motivational enhancement and dual-
`diagnosis relapse prevention psychotherapies described by
`Ziedonis and Trudeau, recent clinical data suggest that
`atypical neuroleptics such as clozapine may help reduce
`substance abuse (Buckley et al. 1994; George et al. 1995;
`Hameedi et al. 1995) and facilitate psychosocial interven-
`tions (Ziedonis and Fisher 1996). This reduction in sub-
`stance abuse is consistent with the rodent studies with
`chronic clozapine administration reviewed earlier in this
`article (Kosten and Nestler 1994).
`Ziedonis and George and (1997, this issue) report on
`a smoking cessation treatment outcome pilot study for
`smokers that have schizophrenia. Improved outcomes
`were seen with the use of nicotine replacement and inten-
`sive psychosocial, twice-weekly, individual motivational
`enhancement therapy and group therapy.
`
`The management of substance abusers with schizo-
`phrenia requires a careful balance of pharmacotherapies
`and psychotherapies. When integrating these two compo-
`nents of therapy, the treatment contact must explicitly
`include monitoring for continued use of illicit drugs or
`alcohol. The usual supportive course of psychotherapy for
`schizophrenia patients includes relatively little limit set-
`ting. In contrast, the treatment of a substance abuser
`involves substantial components of monitoring and limit
`setting. This monitoring requires, at the very least, weekly
`urine toxicologies for illicit drugs, such as cocaine and
`marijuana, as well as breath analysis for alcohol. Patients
`in intensive outpatient or day treatment programs may
`have breath alcohol analysis performed daily. They are
`then given direct feedback in an empathic and nonjudg-
`mental manner about the results of these urine and breath
`analyses, and the treatment is tailored to facilitate docu-
`mented abstinence based on these measures. Achieving a
`goal of abstinence is a process that begins with harm
`reduction and encouraging treatment compliance; main-
`taining a therapeutic alliance is critical.
`Another aspect of limit setting in treatment involves
`the approach to intoxicated patients, particularly those
`participating in group therapy. If patients present for ther-
`apy when intoxicated, they are not allowed to participate
`in the full treatment session because their presence will be
`significantly disruptive to other patients in group treat-
`ment and therapy will not be beneficial to them, whether
`in a group or individually. Instead, these intoxicated
`patients need to be seen for a supportive but firm, brief
`meeting that supports their attempts to reconnect in treat-
`ment, but reinforces their limited ability to do therapy in
`their current state of use or intoxication. During this meet-
`ing, clinicians should perform a brief psychiatric assess-
`ment of their potential for violence or suicidality, as well
`as their possible need of referral to the emergency room
`and hospitalization. If emergency referral is not necessary,
`then another appointment should be set up with the
`patient within the next 24 hours when he or she can be
`seen in a nonintoxicated state. For patients who have not
`been in therapy for several weeks, an assessment of the
`need for medical detoxification may also be necessary.
`Although this need for monitoring and limit setting is
`essential for the management of substance abuse, with a
`schizophrenia patient the amount of confrontation that is
`used for dealing with drug-seeking behaviors needs to be
`carefully titrated. Supportive and psychoeducational ther-
`apies that have been the mainstay of effective work with
`schizophrenia patients continue to be extremely useful for
`the substance-abusing schizophrenia patients. Highly con-
`frontational group processes, which are typically used
`within therapeutic communities for substance abusers
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`T.R. Kosten and D.M. Ziedonis
`
`with personality disorders, have little usefulness in the
`treatment of a substance-abusing schizophrenia patient
`and may precipitate psychotic reactions. The article by
`Wilkins (1997, this issue) integrates supportive and moni-
`toring interventions for optimal efficacy with the sub-
`stance-abusing schizophrenia patient
`An important component of the treatment of the psy-
`chotic substance abuser is management of affect because of
`the role that substance abuse has played in what is often
`called self-medication (Khantzian 1985). From a psycho-
`dynamic perspective, many of these patients find it very dif-
`ficult to manage not only the dysphoria associated with the
`negative symptoms of schizophrenia or neuroleptic side
`effects but also the aggressive urges that are frequently
`magnified during adolescence when initial schizophrenia
`breaks usually occur. Drugs such as alcohol, sedatives, and
`marijuana may significantly dampen aggressive urges in
`these vulnerable adolescents. Drug abuse thereby provides
`a level of self-care that the individual with schizophrenia
`finds impossible to muster without those substances.
`Khantzian (1985) has argued two key aspects of his
`self-medication hypothesis: (1) Abused drugs relieve psy-
`chological suffering, and (2) there is psychopharmacolog-
`ical specificity in an abuser's drug preference. The choice
`of drug is based on its main effects as well as on the indi-
`vidual's personality organization and inner states of psy-
`chological suffering. This psychodynamic perspective
`emphasizes ego deficits and how an individual discovers
`his or her preferred drug through experimentation. When
`the preferred drugs are alcohol and sedatives, the sense of
`isolation, being cut off, and the related anxious states are
`relieved by these sedatives' softening of rigid ego defenses
`(Krystal 1977). In contrast, stimulants appeal to both high-
`and low-energy types to either augment hypomanic states
`or energize the bored, depressed schizophrenia patient. In
`general, substance abusers are considered to experience
`affects in extremes and therefore use drugs to control these
`extremes and to regulate painful feelings. Furthermore,
`subclinical states of distress, not necessarily psychiatric
`disorders, are the important operatives that govern self-
`medication. Even among individuals with schizophrenia,
`Noorsdy et al. (1991) documented that over half experi-
`enced a lessening of social anxiety, tension, dysphoria,
`apathy, anhedonia, and sleep difficulties with alcohol
`abuse. These patients also reported relief of poor interper-
`sonal relationships (42%) and shyness (40%).
`In his formulation of the self-medication hypothesis
`for schizophrenia, Khantzian has emphasized the negative
`symptoms of this disorder (Andreasen 1982a, 19826,
`1990). An interesting observation is that individuals with
`schizophrenia who experience substantial negative symp-
`toms have significantly lower premorbid levels of func-
`
`tioning during childhood and adolescence than those
`without negative symptoms (Kelly et al. 1992). Significant
`suffering and poor interpersonal functioning before the
`onset of schizophrenia could therefore predispose them to
`abuse drugs and alcohol as self-medication. Thus, self-
`medication of the prodroma of schizophrenia might be
`considered important in the association of these two disor-
`ders, even before the onset of substantial negative symp-
`toms of schizophrenia. The treatment implication of this
`hypothesis for the conduct of psychotherapy is the need to
`shore up affect defenses in these patients, which may
`explain the poor efficacy of confrontational substance
`abuse treatments in this population.
`In summary, individuals with substance abuse and
`schizophrenia present as complex clinical cases with mul-
`tiple etiological factors, including genetic predispositions,
`negative symptoms of the disorder that elicit self-medica-
`tion, and neuroleptic-induced side effects. Treatments
`need to involve multiple modalities of psychotherapy and
`possibly atypical neuroleptics or other medication aug-
`mentation strategies. Management of affects along with
`adequate monitoring of drug abstinence, is a key to psy-
`chotherapy. Clinical work with these individuals is ini-
`tially demanding, but can be rewarding and stimulating.
`Realistic treatment goals and skills in appropriate psy-
`chotherapy and pharmacotherapy approaches are impor-
`tant to success. Extensive clinical experience indicates
`that treatment can be helpful; however, research efforts in
`this area must be continued and supported.
`
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`Acknowledgments
`
`This work was supported in part by grants P50-DA04060,
`K02-DA00112 (TRK), K20-DA00193 (DMZ), and P50-
`DA09250 from the National Institute on Drug Abuse.
`
`The Authors
`
`Thomas R. Kosten, M.D., is Professor of Psychiatry, Yale
`University School of Medicine, New Haven, CT, and
`Chief of Psychiatry, Department of Veterans Affairs, VA
`Connecticut Healthcare System, West Haven, CT.
`Douglas M. Ziedonis, M.D., is Associate Professor, Yale
`University School of Medicine, and Director of Dual-
`Diagnosis Treatment and Research, Connecticut Mental
`Health Center, Substance Abuse Center, New Haven, CT.
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`CFAD VI 1025-0006
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