pharmacotherapy of schizophrenia patients with comorbid

Pharmacotherapy of Schizophrenia PatientsWith Comorbid Substance Abuse

by Jeffery N. WMns

Abstract

Substance abuse worsens the course of schizophreniaand significantly impairs the relationship between thepatient and the health care team. Recent advances inlaboratory studies of substance abuse and the pharma-cology of schizophrenia open up new possibilities forpharmacotherapy of substance abuse in schizophreniapatients. D, dopaminergic receptor agonists maydirectly block the drive for stimulant use. D2 dopamin-ergic receptor antagonists may indirectly block thedrive for stimulant and nicotine use, while opioidantagonists appear to reduce the drive to use alcohol.New generations of neuroleptics with serotonin(5-HTj) receptor antagonism and/or 5-HT1A agonistactivity may reduce substance abuse in schizophreniapatients who self-medicate negative symptoms or neu-roleptic side effects. Pharmacotherapy efficacy may beenhanced by adding contingency management, socialskills training, and other manualized programs. Tablesare provided of potentially useful medications.Preliminary results are presented of cocaine-abusingschizophrenia patients treated with desipramlne andtraditional neuroleptics.

Schizophrenia Bulletin, 23(2):215-228,1997.

This review article focuses on the pharmacotherapy ofsubstance abuse problems in patients manifesting schizo-phrenia. Substance abuse, common in schizophreniapatients (Brady et al. 1991; Wilkins et al. 1991; Shaner etal. 1993), worsens the course of schizophrenia and signifi-cantly impairs the relationship between the patient and thehealth care team. For example, substance-induced exacer-bations of psychosis result in frequent hospitalizations forsome patients. Shaner et al. (1995) have described amodel that outlines the contributions of substance abuse tothe "revolving door" phenomenon in individuals withschizophrenia (Haywood et al. 1995). In this model, hos-

pital admission rates for cocaine-abusing patients withschizophrenia are linked temporally with the dispensationof disability checks. When disability funds are givendirectly to such patients, rather than to a representativepayee, the money is used to purchase cocaine. The use ofcocaine exacerbates psychosis, and the patient is subse-quently admitted to the hospital—psychotic and out offunds.

Substance abuse also seems to result in an earlieronset of schizophrenia (Breakey et al. 1974; Alterman andErdlen 1983; Weller and Weller 1986), and amphetamineuse has been linked to the development and maintenanceof psychosis (Baberg et al. 1996; Flaum and Schultz1996). Substances of abuse may also create neurolepticrefractoriness by altering mesolimbic dopaminergic sys-tems (Bowers et al. 1990). In addition to exacerbatingpsychosis, alcohol and cannabinoids seem to aggravateand hasten the appearance of tardive dyskinesia (TD;Dixon et al. 1992; Olivera et al. 1990). Even recreationaluse of marijuana or alcohol may increase the severity ofTD in neuroleptic-treated patients with schizophrenia(Zaretsky et al. 1993).

Recommendations regarding the pharmacotherapy ofschizophrenia patients with comorbid substance abuse arederived from four sources: pharmacotherapy studies ofcocaine abuse in schizophrenia patients, pharmacotherapystudies of substance abuse in patients with non-Axis Icomorbid illness, advances in the pharmacotherapy ofschizophrenia, and advances in the neurosciences. Forexample, although still in an early phase of development,the pharmacotherapy of cocaine abuse and dependence inschizophrenia patients has shown progress. Study resultsat two centers suggest that treatment of schizophrenia incocaine-abusing patients may be enhanced by administer-

Reprint requests should be sent to Dr. J.N. Wilkins, Chief, ClinicalPiychopharmacology Laboratory, West Los Angeles Veterans AffairsMedication Development Unit, West Los Angeles VA Medical Ctr.(116S), 11301 Wilshire Blvd., Los Angeles, CA 90073.

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Schizophrenia Bulletin, Vol. 23, No. 2, 1997 J.N. Wilkins

ing supplementary desipramine (DMI). Additional studiesare progressing on the use in schizophrenia patients ofsupplementary selegiline, a monoamine oxidase (MAO)type B inhibitor; flupcnthixol, a dopamine (DA) D2

autoreceptor and postsynaptic blocker, mazindol (Bergeret al. 1989), a partial DA agonist; and the DA agonistbromocriptine. With support from the National Instituteon Drug Abuse Medication Development Division, levo-alpha-acetylmethadol (LAAM), a long-acting opioidmaintenance medication, and naltrexone, an opioid antag-onist, have recently been approved by the Food and DrugAdministration (FDA) for relapse prevention treatment ofopioids and alcohol. Lists are provided of medicationsthat may serve as useful pharmacotherapy adjuncts in thetreatment of substance-abusing individuals with schizo-phrenia. Some of these medications have already beenapproved for administration to schizophrenia patients asantipsychotic or extrapyramidal symptom (EPS) reducingagents or have been administered to them as part of clini-cal studies. Others are medications approved for treatmentof mental health or medical illness but are under evalua-tion for treatment of substance abuse. Progress attained inthe pharmacotherapy of schizophrenia may also con-tribute to the pharmacotherapy of substance abuse inschizophrenia patients. Novel neuroleptics, includingclozapine and risperidone, may reduce the drive to self-medicate the negative symptoms of schizophrenia or neuro-leptic-induced side effects with substances of abuse.Adjunctive medications that target neuroleptic-induced sideeffects may have the same effect In addition, new classesof agents are being discovered through basic research withthe /V-methyl-D-aspartate receptor complex, the gamma-aminobutyric acid system, and the DA, opiate, and otherneurotransmitter transporter and receptor systems.

Pharmacotherapy Trials of CocaineAbuse and Dependence inSchizophrenia Patients

In the main, pharmacotherapy of cocaine abuse or de-pendence has targeted dopaminergic receptor systemswithin the brain's reinforcement centers (reviewed byKosten 1992). Recent animal research supports thisapproach. Self et al. (1996) have demonstrated that D r

like agonists prevented cocaine-seeking behavior in ratsthat had already received priming doses of cocaine, whileD2-like agonists increased cocaine-seeking behavior.

Discussed below are the results of an open trial and aplacebo controlled, double-blind trial of DMI, a tricyclicantidepressant that blocks dopamine reuptake, adminis-tered to persons who manifested cocaine abuse and schiz-ophrenia or schizoaffective disorder.

DMI. Cocaine-dependent individuals without schizo-phrenia have been shown to reliably reduce ratings ofcraving and improve ratings of depression when adminis-tered DMI (Gawin and Ellinwood 1988). Although furtherstudy has failed to demonstrate DMI-produced abstinencefrom cocaine (Arndt et al. 1992), recent studies suggestthat it may be effective in special populations, such asmethadone-maintained cocaine users (Kosten et al. 1992).In a 12-week open design study, Ziedonis et al. (1992)compared 12 cocaine-abusing schizophrenia patientstreated with 100 to 150 mg of DMI and antipsychoticagents with 15 such patients treated with antipsychoticagents alone. The patients all received social skills train-ing (Liberman et al. 1989) and were given lower dosagesof DMI than usual because its metabolism is altered whenused in combination with neuroleptics (Ziedonis et al.1992). Patients receiving DMI were more likely to com-plete the study (83% vs. 60%), had fewer cocaine-positiveurinalyses during the last 6 weeks of the study (20% vs.50%; 10% vs. 56% during the last month), and had higher6-week (58% vs. 33%) and 4-week abstinence rates (75%vs. 53%). Treatment retention was greater in the DMIgroup than in the no-DMI group (83% vs. 60%), andoverall psychiatric symptoms and signs were reduced.Ziedonis et al. (1996) have extended this work by compar-ing DMI efficacy with the MAO type B inhibitor selegi-line. Selegiline indirectly elevates DA levels and maydecrease cocaine cravings and negative symptoms ofschizophrenia. This 12-week open-label study comparedcocaine-abusing schizophrenia patients treated withselegiline (5 to 10 mg, n = 13), DMI (100 to 150 mg, n =12), or no medication (NOMED; n = 15). Subjects receiv-ing DMI had significandy better outcomes than those inthe selegiline and NOMED groups. For example, 83 per-cent of the DMI group completed the study comparedwith 53 percent of NOMED and 46 percent of selegilinesubjects.

DMI has also been administered in a randomized,double-blind design over 12 weeks to 80 patients withcocaine abuse or dependence and schizophrenia orschizoaffective disorder as determined by die StructuredClinical Interview for DSM-III-R ratings (SCID; Spitzeret al. 1988) (Wilkins et al. 1996). The patients wererecruited following hospitalization for acute psychosis,received DMI for the first 3 weeks as inpatients, and werethen followed for 15 months as outpatients. Before receiv-ing the study medication, the participants were stabilizedon neuroleptics. The dose of DMI was titrated upwardwith yoked adjustments aimed at achieving steady-stateplasma levels between 175 and 250 ng/ml. DMI bloodlevels were performed during the 12 weeks of medicationand 3 additional weeks to monitor washout of the medica-tion.

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The study was conducted as an affiliate investigationof the Clinical Research Center for Schizophrenia andPsychiatric Rehabilitation. The study staff were trainedthrough the Schizophrenia Clinical Research Center withregular determinations of kappa interrater reliability. Allnew study assessment staff received the same trainingbefore conducting assessments. After assessments to con-firm schizophrenia and cocaine dependence by the SCID,assessments were conducted of current psychopathology(Brief Psychiatric Rating Scale [BPRS; Overall andGorham 1962], Beck Depression Inventory [BDI; Beck etal. 1961], Hamilton Anxiety Scale [Hamilton 1959],Scales for Assessment of Negative and PositiveSymptoms [SANS and SAPS; Andreasen 1984a, 1984fe]),medical condition (history and physical exam, blood andurine tests, electrocardiogram, and characteristics ofrecent drug use and psychosocial functioning [AddictionSeverity Index; McLellan et al. 1980]). Assessments alsofocused on whether medication effects persisted once themedication was stopped and whether baseline subjectcharacteristics predicted outcome (Wilkins et al. 1993).

Eighty-seven study participants were entered into thestudy; 80 received study medication. Seventy-three sub-jects (91%) received study medication for at least 2weeks. Seventy-three study participants (91 % of all sub-jects) received study medication for at least 2 weeks, and50 subjects (63%) completed study medication. Analysisof urine levels of the cocaine metabolite benzoylecgonine(BE) revealed an apparent treatment effect during studyweeks 10 to 26 (p = 0.035, general estimated equation).Between weeks 10 and 26, a median of 47 patients (60%of subjects) were evaluated 11 times (weeks 10 to 19 andweek 26). Semiquantitative urine levels of BE were higherin the placebo group in 10 of the 11 visits between weeks10 and 26: They were more than three times as high atweeks 10 and 11, more than four times as high at week17, and more than nine times as high at weeks 19 and 26.Consistent with this finding, Student /-tests revealed sig-nificant or near significant medication group differences atstudy weeks 1 1 0 = 0-07), 17 (p = 0.05), 19 (p = 0.06),and 26 (p = 0.03). (See figures 1 and 2.) Although not sta-tistically significant when compared with the placebogroup, the DMI group had twice the number of negativeurinalyses at weeks 16 and 17 and 1.5 times as many atweeks 18 and 19. There was no difference in retentionbetween the two medication groups. In addition, there wasan interaction between a current visit's log BE and thetotal BDI score at the same visit (p = 0.0O01) and at theprior visit (p = 0.0113), and between a current visit's logBE and the BPRS negative symptom subscale for each ofthe two prior visits (p = 0.0219 and p = 0.0180, respec-tively) (Wilkins et al. 1993).

Figure 1. Mean quantitative urine levels of thecocaine metabolite benzoylecgonine (all visits)

Figure 2. Percent of study participants withnegative urinalyses

These preliminary results suggest that cocaine-abus-ing schizophrenia patients receiving DMI for 12 weeksused less cocaine in a 15-month period than schizophreniapatients who received placebo medication. This decreasein frequency and amount of cocaine use occurred betweenweeks 10 and 26. The timing of this apparent effect is ofinterest, since it extended for almost 2 months after themedication was discontinued. Investigation is under wayto identify individual characteristics of those patients,including their steady state and washout DMI blood lev-

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Schizophrenia Bulletin, Vol. 23, No. 2, 1997 J.N. Willdns

els, who best responded to DMI. Particular focus will beon those study participants who manifested any negativeurinalyses during weeks 10 to 26 (Wilkins et al. 1993).

In a preliminary study drawn from the above popula-tion, Pearson correlation coefficients from 29 of thepatients with urines positive for cocaine and for cocaineand marijuana were characterized as manifesting either"positive" or "negative" correlation between urine valuesand the BPRS, BDI, and SANS scores. Almost all sub-jects in the cocaine only, but not the cocaine and mari-juana group, had positive correlation.with the BDI totaldepression score (12 positive, 1 negative vs. 6 positive, 8negative, Fisher's statistic = 7.334, p = 0.013). A similarbut inverse relationship was found with the BPRS nega-tive symptom subscale (2 positive, 11 negative vs. 7 posi-tive, 7 negative, Fisher's statistic = 3.483, p = 0.103).Conversely, the cocaine only and cocaine and marijuanagroups had similar positive correlation with the BPRShostility/suspiciousness subscale (11 positive and 4 nega-tive, 10 positive and 4 negative, Student t = 2.81, p =0.009). The provisional conclusion from these results wasthat cocaine produces depression in schizophrenia patientsbut may reduce negative symptoms; cocaine and cocaineplus marijuana induce hostility and suspiciousness, butconcomitant marijuana use prevents cocaine-induceddepression. Therefore, patients who develop depressionsecondary to cocaine use may alleviate some of thisdepression with marijuana use. In addition, stimulation ofthe marijuana receptor may ameliorate depression, even inpatients with depleted brain catecholamines.

Imipramine (IMI) and Flupenthixol. In parallel withthe above studies, Siris et al. (1993) extended prior workwith IMI treatment of postpsychotic depression (Siris etal. 1988a, 19886) by administering IMI in an open designto schizophrenia subjects with substance abuse problems.Four of 11 patients receiving IMI were reported to haveimproved significantly, and none worsened in signs orsymptoms of schizophrenia while receiving IMI.Flupenthixol, a depot or orally administered thioxanthenederivative combining DA type 2 (D2) pre- and post-synap-tic receptor blockade has been evaluated in an open-labeltrial by Levin et al. (submitted for publication) for thetreatment of cocaine-abusing schizophrenia patients.Preliminary results in the 4-week inpatient, 6-week out-patient study of eight individuals administered 40 mg offlupenthixol every 2 weeks demonstrate increases incocaine-negative urinalyses and clinic visits, and decreasesin negative symptoms and BDI scores.

Pharmacological Advances in thePharmacotherapy of Substance Abusein Patients Without Schizophrenia

Various forms of substance abuse pharmacotherapy rec-ommended for patients without schizophrenia (AmericanPsychiatric Association 1995) may be applicable to schiz-ophrenia patients. For example, naltrexone, a long-actingopioid antagonist, was recently approved by the FDA foradjunctive pharmacotherapy in the treatment of relapseprevention in alcoholics. Opioid agonists and antagonistshave been used experimentally in individuals with schizo-phrenia since the discovery of beta-endorphin and theenkephalins almost 20 years ago (reviewed by Marchesi etal. 1992 and Welch and Thompson 1994). Similarly, theuse of benzodiazepines for sedative-hypnotic withdrawaldoes not seem to be contraindicated in schizophreniapatients since these agents are recommended for treatmentof their EPS (reviewed by Wolkowitz and Pickar 1991).

Tables 1 and 2 list substances that are being evaluatedor are under consideration for treatment of substanceabuse (reviewed by Ling and Shoptaw, in press). Table 1lists medications that are approved for the treatment ofschizophrenia or that have already been involved in clini-cal studies with schizophrenia patients. Table 2 lists med-ications that are approved for the treatment of mentalhealth or medical conditions other than substance abuse,but that are under evaluation or being considered for sub-stance abuse treatment. Clinicians treating schizophreniapatients should use these medications for treatment ofsubstance abuse only after reviewing FDA guidelines foradministering substances for nonapproved indications. Ofclear concern is the risk of medication interactions (e.g.,adjunctive medications taken to reduce substance use thatalter neuroleptic levels or biological activity) or pharma-cological interactions with abused substances. In addition,contingency management, demonstrated to be a powerfultool in diminishing cocaine use by schizophrenia patients(Shaner et al., in press) and nonschizophrenia patients(Higgins et al. 1994), along with social skills training(Liberman and Corrigan 1993) should be consideredimportant adjuncts to pharmacotherapy.

Self'Medication as a Target forPharmacotherapy

Traditional pharmacological treatment of substance abuseproblems can be divided into seven configurations: (1)

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Table 1. Medications already used In treatment and clinical research of schizophrenia that may alsoassist In treatment of substance abuse (SA)

SA desiredMedication Traditional use SA mechanism of action pharmacological effect

Amantadine

Benzodiazepines

Bromocriptine

Carbamazepine

Dextroamphetamine

Desipramine

Disulfiram

Flupenthixol

Mazindol

Risperidone

Selegiline

Tiapride

Alleviate EPS DA agonist

Alleviate EPS GABA antagonist

Reduce hyperprolactinemia D2 agonist

Treat bipolar illness Anticonvulsant

Reduce negative symptoms Sympathomimetic amine

Prevent cocaine relapse DA, NE reuptake inhibitor

Prevent alcohol relapse

Antipsychotic, antldepres-sant

Anorectic

Antipsychotic

Anti-Parkinson's disease

Antipsychotic

AWehydre dehydrogenaseinhibitorAutoreceptor/postsynapticDA antagonistDA antagonist

D2 and 5-HT2 antagonist

MAOI-B

D2 antagonist

Stimulant relapse preven-tionAlcohol, opioid detoxifica-tionStimulant relapse preven-tionStimulant, alcohol relapsepreventionStimulant relapse preven-tionStimulant relapse preven-tionAlcohol relapse prevention

Cocaine relapse prevention

Stimulant relapse preven-tionStimulant relapse preven-tionStimulant relapse preven-tionAlcohol relapse prevention

Note.—EPS » extrapyramidal symptoms; DA - dopamine; GABA - gamma-aminobutyric add; NE - norepinephrine; D2 - doparrrine type 2; 5-HT2 • sero-tonin-2; MAOI-B » monamine oxkJasa type B inhtortor.

Table 2. Medications already used to treat mental health and medical illness that may also assist intreatment of schizophrenia patients with substance abuse (SA) problems

Medication SA mechanism of actionNon-SA traditional

clinical use

Cocaine treatmentAmoxapineBaclofenBupropionButylcholinesteraseCarbidopa/levodopaErgoloid mesylatesFenfluramineFluoxetineGBR-12909LamotrigineLJsurideMethylphenidateNaltrexoneNefazodonePemolinePergolide

Alcoholism treatmentCalcium acetyihomotaruinateCitalopram

DA agonist; NE and 5-HT reuptake inhibitorGABAb antagonistDA transporter inhibitorIncreases metabolism of cocaineDA precursorD,, D2 partial agonistIncreases 5-HT turnoverSSRIDA transporter inhibitorSodium channel blockerDA partial agonist, 5-HT antagonistCNS stimulantMu opioid antagonistNE antagonist, 5-HT2 antagonistCNS stimulantD v D2 agonist

Analog of GABASSRI

AntidepressantAntispasmAntidepressantMetabolic inductionAnti-Parkinson's diseaseCognitive enhancerAnorecticAntidepressantAntidepressant, anti-Parkinson's diseaseAnticonvulsantAnti-Parkinson's diseaseADHDOpioid, alcohol relapse preventionAntidepressantADHDADHD

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Table 2. Medications already used to treat mental health and medical illness that may also assist intreatment of schizophrenia patients with substance abuse (SA) problems—Continued

Medication SA mechanism of actionNon-SA traditional

clinical use

ClonidineFluoxetineLofexidineNaltrexoneOndansetronPhenobarbitalPhenytoin

Opiates/opioid treatmentMaintenance

BuprenorphineBuprenorphine/naloxoneLAAMMethadone

OthersCaptoprilDextromethorphanLofexidineMemantineNaltrexoneNimodipine

Alpha-2-adrenergic agonistSSRIAlpha-2-adrenergic agonistMu opioid antagonist5-HT3 antagonistCNS depressantSodium channel blocker

Mu opioid agonistMu opioid agonist/antagonistMu opioid agonistMu opioid agonist

ACE inhibitorNMDA receptor antagonistAlpha-2-adrenergic agonistNMDA receptor antagonistMu opioid antagonistCalcium channel antagonist

AntihypertensiveAntidepressantAntihypertensiveOpioid relapse preventionAntiemeticAnticonvulsantAnticonvulsant

Under review by FDAUnder review by FDA1995 FDA approvalMost common form of detoxification andmaintenance

AntihypertensiveAntitussiveAntihypertensiveNone

AntistrokeNote.—DA - dopamlne; NE « norepinephrtne; 5-HT • serotonin; GABA - gamma amfnobutyric acid; D, . dopamine type 1; D2 - dopamine type 2; SSRI -selective serotonin reuptake Inhibitor; CNS • centra) nervous system; ADHD . attention deficit hyperactivity disorder; FDA - Food and Drug Administration;ACE - anglotensln converting enzyme; NMDA - /V-methyl-D-aspartic acid; LAAM - levo-alpha-acetylmetnadol

agonists to substitute for the substance during detoxifica-tion or maintenance (e.g., opioid or nicotine replacement);(2) antagonists (e.g., naloxone, naltrexone); (3) aversiveagents (e.g., disulfiram); (4) anticraving agents; (5) anti-drug-seeking agents (other than anticraving); (6) agentsfor comorbid psychiatric problems (either drug-induced ordrug-independent); and (7) agents for comorbid medicalproblems (either drug-induced or drug-independent). Twoadditional areas may be appropriate for the pharmacother-apy of individuals with schizophrenia who have substanceabuse problems: agents targeting negative symptoms andneuroleptic side effects that target the central nervous sys-tem receptor mechanisms underlying both schizophreniaand substance abuse.

The coexistence of substance abuse and diminishedsubstance abuse has led many investigators to propose thata major motivation for substance abuse in schizophreniapatients is self-medication of negative symptoms(Schneier and Siris 1987), neuroleptic-induced EPS(Treffert 1978; Knudsen and Vilmar 1984; Miller andTanenbaum 1989), or depression (Freed 1975; Siris et al.1993). Because substance-abusing patients manifest lesspsychopathology than non-substance-abusing patients(Mueser et al. 1990; Dixon et aJ. 1991), it has been pro-

posed that drug abuse is a behavior that requires higherfunction and that drug abuse may complicate a less severecase of schizophrenia. For example, in a study of 83 psy-chotic inpatients, approximately half of whom were sub-stance abusers, the 41 patients who did abuse substanceshad less overall psychopathology (per the Global Assess-ment Scale [Endicott et al. 1976], BPRS, and negativesymptom measures) at discharge from inpatient status, yetover the outpatient stabilization phase did no better thanthe non-substance-abusing patients (Dixon et al. 1991). Arecent review of prevalence studies of stimulant abuse inschizophrenia patients (LeDuc and Mittleman 1995) pro-posed that the primary reason for the increased presenceof stimulant use by schizophrenia patients, as comparedwith other diagnostic groups, is self-medication to over-come neuroleptic-associated symptoms.

Stimulant Abuse. Stimulant use, which often arises as aform of self-medication to reduce negative symptoms, hasalso been shown to increase depression (Sevy et al. 1990;Wilkins et al. 1993; Serper et al. 1995). Consistent withthese findings, van Kammen and Boronow (1988)observed attenuation of negative symptoms in schizophre-nia patients receiving intravenous dextro-amphetamine. In

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the study by Serper and colleagues, 15 cocaine-abusingand 22 cocaine-abstaining patients were evaluated withinhours of their last cocaine use and between days 21 and30 of inpatient admission. The schizophrenia patientsusing cocaine were found to have fewer negative symp-toms on the Abnormal Involuntary Movement Scale(AIMS; Guy 1976) and increased anxiety /depression asmeasured by the BPRS. The significant difference in neg-ative signs and mood symptoms at admission was attrib-uted to the neurobiological impact of cocaine. In an ear-lier study (Brady et al. 1990), 17 male cocaine-abusingschizophrenia patients reported using cocaine to elevatetheir mood. After 1 year these patients were hospitalizedmore frequently, were more likely to have a diagnosis ofthe paranoid subtype, and were more likely to bedepressed at the time of interview than the group that didnot use cocaine. There was also a trend toward higherAIMS scores in the cocaine-abusing group (4.3 comparedwith 2.8 for nonabusers), suggesting that chronic cocaineuse may produce a supersensitivity of DA receptors,which could then potentiate the neuroleptic:inducedsupersensitivity that some investigators think is responsi-ble for TD.

Cannabinoids. The effects of marijuana on positive andnegative symptoms of schizophrenia were studied byPeralta and Cuesta (1995). Marijuana-abusing individualswith schizophrenia (n = 23) scored significantly lower onthe alogia subscale of the SANS than nonabusers (n = 72)did, suggesting that schizophrenia patients may use mari-juana to self-medicate negative symptoms. In an earlierstudy (Knudsen and Vilmar 1984), 7 of 10 cannabis-usingschizophrenia patients described initial experiences asfeeling "inspired," "relaxed," "energized," or "active" andsubsequent experiences of feeling "bad" or "aggressive."This finding is consistent with a survey in which 69 of 76schizophrenia patients who used cannabis reportedadverse psychic effects due to cannabis use (Negrete et al.1986). In addition, marijuana use may accelerate theonset of schizophrenia or exacerbate a current episode(Andreasson et al. 1987). For example, in this study(Andreasson et al. 1987) the risk factors in marijuanausers for development of schizophrenia were greater thanthose of nonusers by a factor of 4.

In a study of 93 relatively young patients consecu-tively admitted to the hospital with recent-onset schizo-phrenia—of whom 24 (26%) tested positive forcannabis—patients were assessed at baseline and at a 1-year followup visit (Linszen et al. 1994). The authorsreported significantly more and earlier psychotic relapsesin the cannabis-abusing group. This association becamestronger when mild and heavy abuse were distinguished.

In all but one patient, cannabis abuse preceded the onsetof the first psychotic symptoms for the 1-year period ofstudy. The authors concluded that cannabis abuse, particu-larly heavy abuse, can be considered a stressor elicitingrelapse in patients with schizophrenia and related disor-ders and possibly may be a premorbid precipitant; theyalso reported that the results were not confounded byexposure to alcohol or any other psychoactive drugs, norby differences in antipsychotic medication complianceand dosage.

Although two medications—L-tryptophan andSAAVE, a proprietary supplement made up of amino acidprecursors of DA and serotonin (5-HT)—have been rec-ommended for treatment of withdrawal symptoms fromcannabinoids (Zweben and O'Connell 1992), there is nocontrolled research to support their efficacy.

Nicotine. Over 90 percent of schizophrenia patientsreceiving inpatient treatment in an urban medical centerwere found to smoke cigarettes (Gritz et al. 1985).Schizophrenia patients who smoke have been reported tonormalize schizophrenia-associated auditory dysfunction(Adler et al. 1993) as well as manifest significantly lessneuroleptic-induced Parkinsonism, and a trend for dimin-ished TD as measured by the AIMS (Goff et al. 1992).These findings reflect the central nervous system actionsof nicotine coupled with nicotine's ability to inducehepatic microsomal metabolism of neuroleptics (reviewedby Ziedonis and George 1997, this issue). Consistent withthe metabolic findings, individuals with schizophreniawho smoke have been reported to receive significantlyhigher doses of neuroleptics (Leon et al. 1995).

In a study of 265 outpatients with schizophrenia (n =182) or schizoaffective disorder (n = 83) (Ziedonis et al.1994), smokers had an earlier onset of schizophrenia (age24) than nonsmokers (age 28), had more positive symp-toms of schizophrenia (heavy smokers: 9.1; light smokers:5.5; nonsmokers: 4.3), and were prescribed higher levelsof neuroleptic medication (590 mg of chlorpromazine forsmokers vs. 375 mg for nonsmokers). As might be antici-pated from the findings with individuals with schizophre-nia who use cocaine or amphetamines, the heavy smokersalso had less negative symptoms (5.9 compared with 7.0for light smokers and 7.2 for nonsmokers).

Regarding treatment, schizophrenia patients wearinga nicotine-containing skin patch have been found tosmoke significantly less than when wearing a placebopatch (Hartman et al. 1991). (The use of the nicotinepatch has been summarized by the American PsychiatricAssociation 1996.) Patients successfully treated with thepatch will likely require a lowering of neuroleptic dose asthey smoke less. Interestingly, traditional neuroleptics

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have been found to diminish cigarette smoking in non-schizophrenia patients (Caskey et al., in press).

Caffeine. Schizophrenia patients may ingest coffee as aform of self-medication but with attendant risks. Forexample, Hyde (1990) has demonstrated that there aresubgroups of schizophrenia patients who require increas-ing doses of neuroleptic to "cover" coffee effects.

The pharmacological treatment of choice for individ-uals wishings to stop or attenuate caffeine use is a rapidlytapering regimen of caffeine; as yet there is no viablepharmacological substitute to offset caffeine withdrawaland diminish caffeine craving (Greden and Walters 1992).The rationale for this approach is empirical, with supportfrom the demonstration that coffee drinkers, after a weekof drinking decaffeinated coffee, had no preference forcaffeinated over decaffeinated coffee (Griffiths et al.1986). Based on this approach, an individual who drinkssix cups of coffee per day could be placed on the follow-ing 6-day tapering regimen: first day—five cups caf-feinated coffee/one cup decaffeinated; second day—fourcups caffeinated coffee/two cups decaffeinated; and soforth to the sixth day—no cups caffeinated coffee/six cupsdecaffeinated. The recommendation is detoxification tocomplete abstinence, since abstinence seems to be moreeffective in preventing relapse than reduction (Greden andWalters 1992). Caffeine pills may be substituted, espe-cially for those with severe caffeine dependence of 1 gramper day or more than eight cups of coffee per day. Treat-ment should also include education about the adverse con-sequences of chronic caffeine use and the various prod-ucts and medications that contain caffeine. By havingwater and perhaps some sugarless mints readily available,the client may be better prepared to manage and alleviatecraving.

Alcohol. Studies of the DA metabolite homovanillicacid (HVA) in individuals with schizophrenia should con-trol for the use of alcohol because low HVA levels havebeen found in male alcoholics who have been abstinentfor 3 weeks (Fulton et al. 1995). These findings also sug-gest that agents altering dopaminergic systems may proveuseful in the treatment of schizophrenia patients whoabuse alcohol.

While disulfiram has been used extensively withpatients manifesting schizophrenia, naltrexone may also beuseful for this population. Recently approved by FDA foralcohol relapse prevention, naltrexone may help schizo-phrenia patients who have attained abstinence from alco-hol. The FDA approval was based largely on studies fromVolpicelli and colleagues (1992) at the PhiladelphiaVeterans Affairs Medical Center substance abuse programs

and O'Malley and colleagues (1992) at the Yale substanceabuse programs. Volpicelli et al. (1992) demonstrated in adouble-blind study of 70 alcohol-dependent-only subjectsthat those who received naltrexone had significantly fewercravings and a significantly lower rate of relapse than thosewho received the placebo. In addition, naltrexone treat-ment had no effect on psychopathological condition asassessed by the BPRS and the Hopkins SymptomChecklist-90 (SCL-90; Derogatis et al. 1973). Further-more, naltrexone, as compared to placebo, significantlydecreased the relapse rate for drinking once an individualhad "slipped" (consumed any alcohol). In another studyassessing the effects of natrexone and coping skills or sup-portive therapy versus only coping skills or only support-ive therapy, relapse rates for those receiving the medica-tion plus therapy were again significantly lower than thosereceiving therapy only (O'Malley et al. 1992). The authorsconcluded that naltrexone was significantly superior toplacebo, regardless of therapy received, on several treat-ment variables, including number of drinks consumed,abstinence and relapse rates, and problem severity as mea-sured by the Addiction Severity Index on alcohol, drug,and employment problems.

Although there were early reports that the use ofdisulfiram is correlated with psychosis (Liddon and Satran1967), within narrow limits, it has been demonstrated tobe effective and safe in schizophrenia patients (Kofoed etal. 1986). The narrow limits are imposed due to disulfi-ram's apparent ability to increase central nervous systemlevels of DA, possibly through its blockage of DA betahydroxylase, the enzyme that catalyzes the conversion ofDA to norepinephrine. Kingsbury and Salzman (1990)noted that patients at least 40 years old and able to remainin psychiatric treatment despite a long history of alcoholabuse seem to be good candidates for treatment withdisulfiram. Patients should not be acutely psychotic;should not have signs of organic mental impairment,depression, or impulsive behavior; and should be legallycompetent and able to give informed consent. They shouldalso have demonstrated compliance with other medica-tions and should be in a stable treatment program. Thetypical recommended daily dose is 250 to 500 mg, butlower doses seem to have fewer side effects. Disulfirammay interact with other drugs taken by individuals withschizophrenia because it increases the metabolism of neu-roleptics. The authors note the absolute contraindicationof pregnancy and relative contraindications of myocardialdisease, liver disease, chronic renal failure, pulmonaryinsufficiency, and asthma.

Kofoed et al. (1986) reported the successful use ofdisulfiram with schizophrenia patients (reviewed byGalanter et al. 1988). Thirty-two patients with coexisting

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substance abuse and other psychiatric disorders weretreated in an outpatient pilot program that used techniquesdrawn from both psychiatric and substances abuse treat-ment. Eleven patients remained in treatment for 3 or moremonths, and 7 completed a year or more of treatment.(Specific pharmacotherapies were not the main focus ofthis article, but a few important results involving disulfi-ram can be found in table 2.) No complications werereported in routine disulfiram administration to the duallydiagnosed population. Overall disulfiram compliance ratesand individual patterns of compliance were reported to bealmost identical to those reported in alcoholics withoutother psychiatric illness.

Contributions to the Pharmacotherapyof Substance Abuse Arising FromAdvances in the Medication Treatmentof Schizophrenia

Neuroleptics or other pharmacological agents that im-prove negative symptoms, target impaired affect (Hogartyet al. 1995), or reduce traditional neuroleptic side effectsmay reduce the drive for self-medication. For example, areliable association has been made between use of tradi-tional neuroleptics and stimulant abuse in schizophreniapatients (LeDuc and Mittleman 1995).

Recent neuroscientific evidence strongly suggests thatthe DA receptor (D^ is the primary receptor for reinforce-ment of cocaine and other substances of abuse. Thus, theideal medication for pharmacotherapy of a stimulant-abus-ing schizophrenia patient would lessen negative symptomswhile simultaneously targeting both the D, (reducing thedrive to use cocaine) and D2 receptors, the latter beinglargely responsible for the positive symptoms of schizo-phrenia. Clozapine seems to be the prototype for this idealagent. It has D, blocking activity, with minimal D2 block-ing supplemented by blockade of serotonin-2 (5-HT2)receptors. Clozapine has been shown to improve negativesymptoms (Nordstrom et al. 1995) and thus may reducethe drive to self-medicate with substances of abuse.Although clozapine's ability to treat substance abuserequires further study, Buckley et al. (1994a, \994b) havedemonstrated that substance abusers and nonabusersshowed similar improvements on measures of psy-chopathology and psychosocial functioning after 6 monthsof clozapine therapy. Two other neuroleptics that sharemixed 5-HT2/D2 antagonism are risperidone and remox-ipride. Risperidone has been shown to inhibit phencycli-dine (PCP)-induced stereotyped behaviors in rats in com-parison with haloperidol and ritanserin, but with DAmetabolite levels demonstrating less D2 activity than

haloperidol. Flupenthixol, a medication that may reducecocaine craving (Gawin et al. 1989), balances D, with D2

activity (Soyka and Sand 1995).The 5-HT system inhibits dopaminergic function at

the level of the origin of the DA system in the midbrain,as well as in the terminal dopaminergic fields in the fore-brain (Kapur and Remington 1996). Serotonergic antago-nists release the DA system from this inhibition. This dis-inhibition may alleviate neuroleptic-induced EPS, and asimilar disinhibition in the prefrontal cortex may amelio-rate negative symptoms. Serotonergic modulation ofdopaminergic function is a viable mechanism to be ex-plored for enhancing therapeutics in schizophrenia pa-tients. There is evidence for a clear role for 5-HT3 recep-tors in the modulation of activity of mesolimbic andmesocortical DA neurons. Antagonists to the 5-HT3

receptor may have potential as novel antipsychotic agentsand in treating psychoactive substance abuse (Hagan et al.1993). They may prove to be among the first agents avail-able to treat schizophrenia that are not D2 antagonists andhence lack their side effects.

Although prior studies have failed to demonstrate theefficacy of neuroleptics in treating cocaine abuse inhumans (Gawin 1986), a recent study by Berger et al.(1996) illustrates the potential importance of blocking DAreceptors for attenuating the physiological and neuroen-docrine effects of cocaine-related cues. Reexposure toenvironmental cues (e.g., pharmaceutical aromas ormoney) associated with cocaine use can trigger cravingand drug-seeking behavior. This craving may persist longafter the period of initial drug abstinence (Gawin andKleber 1986), thereby increasing the risk of relapse(Childress et al. 1992). In a study evaluating the role ofDA release by such cues, 20 male cocaine-dependent, vet-eran inpatients were randomized in a single-dose,crossover, placebo-controlled design to haloperidol (4 mgby mouth) and placebo (Berger et al. 1996). Plasma HVA,the principal DA metabolite, adrenocorticotrophic hor-mone (ACTH), and cortisol were assayed before and aftercue (videotape) exposure. Craving and anxiety were alsomeasured before and after cue exposure with visual ana-log scales. Cocaine cues significantly increased levels ofanxiety, ACTH, cortisol, and HVA. Increases in anxietyand craving were significantly antagonized by pretreat-ment with haloperidol. Although the side effect profile ofhaloperidol makes it unlikely to be of value in patientswho do not have schizophrenia and, for that matter, cre-ates problems in schizophrenia patients, the cocaine cue-reactivity model may illustrate a mechanism relevant tothe pharmacotherapy of stimulants and other drugs ofabuse. Shorter-acting, better-tolerated DA antagonists ordrugs that inhibit DA release may merit attention.

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Adding anticholinergic medication, especially in theacute phase of psychosis (Tandon and DeQuardo 1995,referring to Goff et al. 1995), seems to lessen negativesymptoms significantly (Garcia 1991). The addition of r>cycloserine to conventional neuroleptics seems to improvenegative symptoms in schizophrenia patients for whomthese symptoms are dominant (Goff et al. 1995). At a doseof 50 mg/day, D-cycloserine reportedly produced reduc-tions in negative symptoms, and improved reaction times.In this preliminary study, the authors concluded that D-cycloserine may improve negative symptoms and cognitivedeficits over a narrow dose range when added to conven-tional antipsychotic agents. As discussed in the followingsections, reduction of negative symptoms may lessen thedrive for self-medication with substances of abuse byschizophrenia patients.

Summary

Five themes have been discussed in this review: (1) Thephenomenology of schizophrenia influences the patient'schoice of substance, timing and amount used, and moti-vation for substance abuse treatment. (2) Schizophreniapatients use stimulants (cocaine, amphetamine, caffeine),cannabinoids, nicotine, and alcohol, partly to self-med-icate the negative symptoms of schizophrenia or adverseexperiences of neuroleptic treatment. (3) Self-medicationwith substances of abuse is only transiently effective,with subsequent development of untoward results, includ-ing depression, anxiety, and worsening of positive symp-toms. (4) To be optimally successful, pharmacotherapy ofschizophrenia patients with substance abuse problemsmust be combined with manual-based psychosocialstrategies including contingency management of disabil-ity funds and social skills training. For example, contin-gency management of disability monies through the useof payees could be performed in concert with pharmaco-therapy aimed at reducing substance abuse. (5) Pharmaco-therapy with D, DA receptor agonists and partial D2 DAreceptor blockade may reduce the drive to use stimulantsand nicotine; and the use of neuroleptics with 5-HT2

receptor antagonism or 5-HTfA agonist activity mayreduce substance abuse in schizophrenia patients whoself-medicate.

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Acknowledgments

This study was supported by National Institutes of Healthgrant ROl DA-06551 and the Veterans Affairs MedicationDevelopment Unit Program from the National Institute onDrug Abuse. The author expresses his appreciation toDavid A. Gorelick, M.D., Ph.D., and acknowledges thefollowing individuals who participated in either the med-ication administration, laboratory, or psychosocial compo-nent of the Desipramine Treatment Program: Jeff Gold,Valerie VonRaffay, Ph.D., Dawn Levine, Ph.D., DaveSetoda, Azita Ashofteh, Sabrina Lee, Andrew Shaner,M.D., Douglas Tucker, M.D., Thad Eckman, Ph.D., andLisa Roberts.

The Author

Jeffery N. Wilkins, M.D., is Chief, Clinical Psycho-pharmacology Laboratory, West Los Angeles VeteransAffairs Medical Center (VAMC) Medication Develop-ment Unit, and Medical Director, ComprehensiveHomeless Programs, West Los Angeles VAMC, andProfessor of Psychiatry and Biobehavioral Sciences,University of California School of Medicine, LosAngeles, CA.

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