Antidepressant for substance-abusing schizophrenic patients: A minireview

Pro& Nauro-Psychopharmocol. & Bwf. Psychiut. 1991, Vol. 15. pp. l-13 Printed in Great Britain. All rights reserved

027~5846/91 $0.00 + so IQ 1991 Pergamon Press plc

ANTIDEPRESSANT FOR SUBSTANCE-ABUSING SCHIZOPHRENIC PATIENTS: A MINIREVIEW SAMUEL G. SIRIS, PAUL C!. BERMANZOHN, SUSAN E. MASON AND MITCHELL A. SNUNALL Hillside Hospital Division of the Long Island Jewish Medical Center and Albert Einstein College of Medicine, New York, N.Y. U.S.A. (Final form, October 1990) Contents 2. 2. 3. 4. 5.

Abstract Introduction Antidepressant Medications in Schizophrenia Propensity for Substance Abuse Among Depressed Schizophrenic Patients Indications of Outcome When Antidepressants are used in SubstanceAbuse-Prone Schizophrenic Patients Conclusions Acknowledgements References

1 2 2 6 7 9 9 9

Abstract Siris, Samuel G., Paul C. Bermanzohn, Susan E. Mason and Mitchell A. Shuwall: Antidepressants for Substance-Abusing Schizophrenic Patients. A Minireview. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1991, 13 (1): l-13. 1.

Substance abuse and post-psychotic depression are both frequently encountered concomitants of schizophrenia.

2.

Substance abuse may be associated with depression-like s~ptomatology in the course of schizophrenia, and patients may attempt to selfmedicate these symptoms with substances of abuse.

3.

Antidepressant medication has been found to be a useful adjunct to treatment in at least some cases of substance abuse and some cases of post-psychotic depression.

4.

Preliminary evidence exists suggesting that adjunctive antidepressant medication, added to a neuroleptic, may be useful for at least some stable dysphoric substance-abusing schizophrenic patients.

5.

It is important to attempt to rule out even subtle neuroleptic-induced akinesia in such patients with a vigorous trial of antiparkinsonian medication.

&e_ywords: antidepressant medication, depression, schizophrenia, substance abuse. &&eviations: analysis of covariance (ANCOVA), by mouth (PO), number (N), Research Diagnostic Criteria (RDC), three times per day (TID).

S. G. Siris et al.

1.

Introduction

A body of evidence has begun to accumulate that antidepressant medications may prove

to be

an effective

component

of treatment

for at

least

some

subjects who suffer from substance abuse (Resnick and Resnick 1984: Gawin and Kleber 1986; Giannini et al. 1986; Kosten 1989; Pollack et al. 1989).

In

particular, these may be persons who suffer from dysphoria or an affective diathesis,

who

become

involved

in the

abuse

of psychostimulant

agents.

Simultaneously, reports have appeared indicating that there may be a role for the judicious use of adjunctive antidepressant medications in schizophrenia (Singh et al. 1978, Prusoff et al. 1979, Siris et al. 1987, Siris 1990). These

favorable

reports

have

dealt

with

relatively

stable,

neuroleptic-

maintained schizophrenic patients, who exhibit a depression-like

syndrome.

Such depression-like syndromes have been noted to occur not infrequently in schizophrenia - a modal estimate being that they may occur in 25% of cases (McGlashan and Carpenter 1976, Weissman et al. 1977, Falloon et al. 1978, Knights et al. 1979, Roy 1980, Johnson 1981, Mandel et al. 1982, Iiogarty and Munetz 1984, Martin et al. 1985).

Since substance abuse, particularly with

psychostimulant agents, has been observed to occur frequently among patients with schizophrenia (Breakey et al. 1974, McLellan and Druley 1977, Richard et al. 1985, Schneier and Siris 1987, Drake and Wallach 1989, Test et al. 1989)‘ and. since such abuse may predispose their psychoses

these patients to reexacerbations

of

(van Kammen et al. 1977, Gold and Bowers 1978, Angrist and

van Kammen 1984, Richard et al. 1985, Lieberman et al. 1987), a review of the literature relevant to the issue of the use of antidepressant medications in the treatment of substance-abusing schizophrenic patients is warranted. This review will consist of three parts: medications

in depressed

schizophrenic

1) the use of antidepressant

patients,

2) the propensity for substance abuse among depressed schizophrenic patients, and 3) indications

of outcome when adjunctive antidepressants are used in substance-abuse-prone schizophrenic patients. 2.

Fntidenressant Medications in Schizouhrenig

For many years, clinical wisdom dictated that antidepressant medications were

contraindicated

in schizophrenia.

This

impression

was

based

on a

limited series of trials, early in the history of psychopharmacology, which had either used antidepressant medications without a concomitant neuroleptic or

which

had

not

symptomatology. questionable

selected

schizophrenic

patients

with

depression-like

A number of early negative reports also either utilized

diagnostic

criteria

accounts which did not employ confident conclusion

by

modern

standards

or

were

suitable controls which would

(Siris et al. 1978).

anecdotal

allow

for a

Antidepressants

for schizophrenic

3

substance-abuse

recently, as shown in Table 1, there have been nine randomized, double-blind, placebo controlled trials of adjunctive antidepressant medication added to the neuroleptic treatment of depressed-appearing schizophrenic patients (Siris 1990). All of these studies hava involved cyclic antidepressants. Appropriate studies involving MAO-inhibitor type antidepressants have not as yet been reported (Brenner and Shopsin 1980). Four of these cyclic antidepressant studies were positive, indicating that the antidepressant was helpful. The other 5 were negative, not finding utility to the adjunctive antidepressant. These seemingly contradictory studies differed in their methodology,however, so that it may be possible to begin to draw certain conclusions. More

Table 1 Randomized, Double-Blind, Placebo-ControlledTrails of Adjunctive Antidepressants in "Post-PsychoticDepressedtg Schizophrenic Patients Studv

Neurolentic

Antidenressant

Result & Comment

Singh et al 1978

Continued on previous neuroleptic

Trazodone 300 mg/day

Some benefit

Prusoff et al 1979

Perphenazine

Amitriptyline 100-200 mg/day

Some benefit

Siris et al 1987

Fluphenazine decanoate

Imipramine 200 mg/day

Substantial benefit

Siris et al 1989a,1990

Fluphenazine decanoate

Maintenance Imipramine

Substantial benefit

Waehrens & Gerlach 1980

Continued on previous neuroleptic

Maprotiline 50-200 mg/day

No benefit

Johnson 1981

Fluphenazine decanoate Nortriptyline or flupenthixol decanoate I50 mg/day

No benefit

Kurland h Nagaraju 1981

Chlorpromazine or haloperidol

Viloxazine 300 mg/day

No benefit

Becker 1983

Chlorpromazine or thiothixene

Imipramine 150-250 mg/day

No benefit

Bupropion 150-750 mg/day

No benefit

Dufresne et al Thiothixene 1988

The first positive study was that of Singh et al. (1978). In that report, 60 chronic hospitalized patients who met Feighner criteria for schizophrenia (Feighneret al. 1972) and who had Hamilton Depression Rating Scale (Hamilton 1960) scores of 18 or more were randomized to a 6-week trial of trazodone or placebo being added to their previous phenothiazine. This study found the

S. G. Sifis et al.

4

Hamilton Depression Rating Scale scores to be more reduced in the trazodone group, and the clinical global impression scale score also favored the trazodone-treated patients, although the rating changes on the Brief Psychiatric

Rating

Scale

(Overall

and

Gorham

1962)

did

not

achieve

statistical significance. Prusoff et al. (1979) described a study involving outpatients who met New Haven Index criteria

for schizophrenia

(Astrachan et al. 5972) and had a

score of at least 7 on the Raskin Depression Rating Scale 1970).

Amitriptyline

(Raskin et al.

(LLOO-200mg/day) or placebo was added to the patients'

perphenazine regimen (16-48 mg/day), and some patients were followed for as long as 6 months.

The authors found some decrease in depression ratings in

the amitriptyline-treated

group, although that group also had some increase

in thought disorder ratings.

The overall impression, however, was that the

effect of the addition of the amitriptyline was mildly positive, and that many patients benefitted somewhat, rather than just a few achieving great benefit. The most strongly positive Siris et al. (1987). Criteria

findings to have been reported are those of

In this trial, 33 patients who met Research Diagostic

(RDC) (Spitzer et al. 1978) for schizophrenia or schizoaffective

disorder at the time of their most recent flagrant psychotic episode, and who currently were either nonpsychotic or only residually psychotic but who met RDC for major or minor depression

in 'lcross-section,llwere maintained

on

fluphenazine decanoate end benztropine 2 mg po TID while they underwent a 6week trial of imipramine (200 mg/day) or placebo.

The imipramine group was

found to have a statistically superior outcome on the global outcome measure on each of 4 depression subscales. treatment groups

No difference was found between the two

in terms of measures

of psychosis

or side effects.

Of

interest is that this is the only study, of those which have been reported, which

made

an

operationalized

neuroleptic-induced

attempt

akinesia with

a trial

to

eliminate

the

confound

of antiparkinsonian

of

medication

(Rifkin et al. 1975, Van Putten and May 1978, Siris 1987). Patients responding favorably to imipramine in the above study were then included

in

the

double-blind

only

maintenance

study

of

adjunctive

antidepressant in depressed schizophrenic patients which has been reported in the literature (Siris et al. 1989a, Siris et al. 1990). decanoate

and

openly with

benztropine

adjunctive

treatment

imipramine

maintained,

for 6 months

With fluphenazine

patients before

were

continued

either having the

imipramine blindly maintained or tapered back to placebo for another year's treatment.

All of the 6 patients tapered to placebo relapsed into a depression-like state again, vs only 2 of the 8 who were maintained on active All relapsing patients then went on to respond imipramine (p = 0.009).

Antidepressantsfor schizophrenicsubstance-abuse

favorably once again when a tricyclic antidepressant was openly added. The first controlled double-blind of an antidepressant medication

study to

finding no benefit to the addition

depressed schizophrenic patients Was that

of Waehrens and Gerlach (1980). No specific diagnostic criteria were given, although the patients were clearly chronic and emotionally withdrawn. While continuing on their previous neuroleptic, these 17 patients showed no benefit to the addition of maprotiline (50-200 mg/day) in an S-week cross-over design trial.

In

this

the

study,

critique

can

be

raised

that

the

dose

of

maprotiline may have been too low, since in many cases it was lower than that which would be expected to be useful in primary depression. Sohnson (1981) studied 50 chronic schizophrenic patients having Feighner or Scheiderian symptoms, all of whom also had Beck DepreSSiOn (Beck et al. 1961) of 15 or more. fluphenazine decanoate double-blind antidepressant

trial was

InVentOry

SCOreS

While these patients were maintained on

or flupenthixol decanoate, they underwent a 5-week

of not

nortriptyline

150

found to alleviate

mg/day

or

depressive

placebo.

symptoms,

effects were found to be worse in the nortriptyline group.

This and side

One problem in

interpreting this study, however, is that the nortriptyline dose. may have been too high to have its maximum opportunity for efficacy. an antidepressant thought

of its plasma concentration would be expected

Nortriptyline is

to have a therapeutic "window@*of efficacy in terms (Glassman et al. 1985).

to carry many patients

A dose of 150 mg/day

above the upper

window, an effect which might be further exacerbated

limit of that

by the tendency of

concomitant neuroleptic to raise plasma tricyclic levels (Siris et al. 1982). Unfortunately, plasma nortriptyline levels were not obtained in this study, so that the therapeutic window hypothesis remains untested in this group. Kurland and Nagaraju (1981) studied 22 schizophrenic patients (no criteria given) who had Hamilton Depression Rating Scale scores of 18 or more and who were being maintained on chlorpromazine or haloperidol.

Patients receiving

antiparkinsonian medications were specifically excluded.

A 4-week trial of

viloxazine (Up to 300 mg/day in the final week only) or placebo was administered, and the investigators found that both groups improved equivalently. It is Unclear whether this short a trial, built up to a full therapeutic dose in only the final week, constitutes an adequate test of the treatment. Becker (1983) compared the combination of chlorpromazine

(100-1200 mgfday

plus imipramine (150-250 mg/day) with thiothixene alone (5-60 mg/day) over 4 weeks of aCUtS treatment syndrome superimposed

in 52 patients meeting RDC for major depressive

on schizophrenia.

equally effective compared autonomic side effects in

with the

He found both treatments to be baseline, but found more sedative and chlorpromazine/imipramine treated group.

Interpretation of this study is difficult for our purposes, of course, due

6

S. G. Siris et ul.

the fact that different neuroleptics were used for the group which did versus the group which did not receive the antidepressant. Finally, the combination

of thiothixene

plus either bupropion

(150-750

mg/day) or placebo was tested over 4 weeks by Dufresne et al. (1988) among 38 patients

meeting

DSM-III

criteria

atypical affective disorder.

for

schizophrenia

with

superimposed

Both groups improved, although the placebo-

treated group appeared to improve more, and after the 4 weeks the majority of the bupropion-treated patients dropped out of what was scheduled to have been a longer

study.

In summary, although the results have been somewhat mixed, the studies with the

stronger

designs

have

seemed

to

show

at

least

some

evidence

of

improvement when adjunctive antidepressants are added to neuroleptic agents in the treatment of stable non-psychotic schizophrenic patients.

The same

may well not be true for schizophrenic patients who remain actively psychotic at the time of the trial. blind

study

which

has

In this case the one placebo-controlled, doublebeen

reported

showed

no

useful

improvement

in

depressive symptomatology with the addition of adjunctive antidepressant and a

tendency toward exacerbation of the psychotic state (Kramer et al 1989).

Another

important

secondary

issue

depression

induced akinesia,

is

the

differential

in schizophrenia

which

can

be

such

diagnosis

from the a close

which

syndrome

clinical

separates

of neurolepticphenocopy

of the

secondary depressed state (Rifkin et al. 1975, Van Putten and May 1978, Siris 1987). 3.

for Substance Abut2

prODenSitV

DeDressed SCweniC

Although the association of substance abuse with affective disorder and other

dysphoric

states

has

been

well

described

among

nonschizophrenic

patients (Resnick and Resnick 1984, Khantizian 1985, Gawin and Kleber 1986, Mirin and Weiss 1986), few investigations of this relationship exist among patients with schizophrenia.

This is all the more remarkable when one con-

siders the high prevalence of substance abuse which has come to be recognised among schizophrenic patients (Drake and Wallach 1989, Test et al. 1989) and the potential associated

for exacerbation

of psychosis with which such abuse may be

(Snyder 1973, Janowsky and Davis 1976, van Kammen et al. 1977,

Gold and Bowers 1978, Angrist and van Xammen

1984, Richard

et al. 1985,

Lieberman et al. 1987). One

line

schizophrenia

of

evidence

which

would

suggest

such

an

association

in

involves that choice of agents which schizophrenic patients

seem to choose to abuse.

By intuition, one might suspect that schizophrenic

individuals might choose to abuse compounds which are more sedative, since social withdrawal

is such

a common

feature of their disorder

and

since

Antidepressants

for schizophrenic

substance-abuse

7

circumstanceswhich arouse anxiety seem to bring them both discomfort and an Furthermore, there is increased risk of psychotic symptomatology. physiological reason to suppose that psychostimulantsmight directly tend to exacerbate psychosis by their effects on the biogenic amine neurotransmitter systems with which they interact. Nevertheless,the systematic observationhas been otherwise. Schizophrenic patients apparently tend to abuse psychostimulantsubstances preferentially. In a review of the relevant literature, the substances most consistently found to be abused by schizophrenic patients were amphetamine, cocaine, cannabis, and hallucinogens (Schneier & Siris 1987). In this same article, 4 out of the 5 studies reviewed found sedative hypnotics to be significantly less abused by schizophrenic patients than by other groups, with the fifth study showing no difference. This observation supports a self-medication hypothesis of drug abuse in schizophrenia, in which at least one driving force behind the substance abuse may be the individual's attempt to rid himself of unpleasant sensations such as dysphoria, anhedonia, or anergia. These experiences are the very ones which may be prominent aspects of secondary depression in schizophrenia, although anhedonia and anergia can also certainly be important aspects of the negative symptom state in schizophrenia (Crow 1980, Andreasen and Olsen 1982, Carpenter et al. 1985, Pogue-Geile and Zubin 1988), a state with which secondary depression can easily be confused (Siris et al. 1988a). One study was undertaken which specifically examined patients with the syndrome of secondary depression in schizophrenia for the existence of past histories of substance abuse (Siris et al. 198833). That study found a 35% occurrence of previous history of substance abuse among schizophrenic patients with syndromally documented episodes of post-psychotic depression. The most common substance of abuse in that study was cannabis. Tied for second as the most commonly abused substances, however, were two powerful psychostimulants:cocaine and amphetamine, each having been abused by 13% of the subjects studied. Much further down the list were sedatives and opiates, having been abused by only 4% and 2% of the study sample respectively. This study, therefore, is consistent with the psychostimulant self-medication hypothesis concerning substance abuse among dysphoric schizophrenicpatients. 4.

Indications of Outcome When Antidevresmts are Used in Substance-Abuse-ProneSchizoohranic Patients

It is noteworthy in the context of this review that a history of substance abuse did not adversely affect the responsiveness of a series of postpsychotic depressed schizophrenic patients to an adjunctive antidepressant which was added to their neuroleptic/antiparkinsoniandrug regimen (Siris et

S. G. Siris et 01

al. 1988b, Siris et al. 1989b).

In that series, 21 stabilized schizophrenic

or schizoaffective patients, with histories of substance abuse and current operationalized blindly

criteria

assigned

to

for post-psychotic

have

either

depression,

imipramine

or

fluphenazine decanoate and benztropine regimen.

were randomly and

placebo

added

to

their

The global outcome results,

which favored the imipramine-treated group, are shown in Table 2.

Although

the N in this study was relatively small, so that statistical significance was

difficult

to

achieve,

imipramine with statistical

one

of

4

depression

subscales

also

favored

significance and a second depression subscale

favored imipramine with trend-level significance.

Outcome change measures of

psychosis, however, did not differ meaningfully. Table 2 Results of a Double-Blind Trial of Adjunctive Imipramine Involving 21 Stabilized Post-Psychotic Depressed Schizophrenic or Schizoaffective Patients with Histories of Substance Abuse Imipramine-Treated Group (N=14) Clinical Global Impression (CGI) Score (Guy 1976)

Placebo-Treated Group (N=7) a 3.43 + 0.79

2.53 & 0.52

a Results favor imipramine-treated group, t= -3.26, df = 19, p =: 0.004. The above-described

trial of adjunctive antidepressant

in post-psychotic

depressed schizophrenic patients with histories of substance abuse provides the clearest indication in the current literature that antidepressants may be of use in the treatment of relatively stable substance-abuse-prone dysphoric schizophrenic patients.

Furthermore, preliminary, more anecdotal indications

have begun to accumulate that adjunctive antidepressant medication may have a role in the treatment of dysphoric schizophrenic patients who have more recently, or who are currently abusing psychostimulant substances (Mason, S.E., personal communication). file), nine

current

or

In an as yet unpublished recent

substance-abusing

trial

(Siris, data on

dysphoric

schizophrenic

patients have been treated with adjunctiye imipramine (150-200 mg/day) added to their ongoing regimen of fluphenazine decanoate and benztropine. Four of these patients

were rated as being either "much improved" or "very much improved" following their g-week trial, although one of the remaining 5 patients needed to be rehospitalized for a reexacerbation of psychosis, which was subsequently controlled by an increase of neuroleptic medication.

BY way

9

Antidepressants forschizophrenic substance-abuse

of comparison, 3 of the patients in this series had had double-blind placebo In none of these placebo trials which preceded their imipramine treatment. trials were any of the patients considered to be either much or very much improved.

This

anecdotal

series,

conclusions to be based on it.

of course,

is far too

small

for any

It was nevertheless intriguing to note that

a preliminary ANCOVA analysis, covarying for baseline, of visual analogue scales assessing

cocaine

craving

favored the imipramine-treated

at the

end of the double-blind

trial,

group in terms of reduction of craving, as

shown in Table 3. Table 3 ANCOVA, Covarying for Baseline, of Visual Analogue Scale Ratings of Cocaine Craving for Substance-Abusing Post-Psychotic Depressed Schizophrenic and Schizoaffective Patients

Visual Analogue Scale Ratings

Imipramine Treated (N = 6)

Placebo Treated (N = 3)

a 11.4 + 8.8 (S.E.)

67.1 +

12.4

a Results favor imipramine-treated group, F = 13.5, P = 0.01. 5.

Conclusions

On the basis of the data here reviewed, it is fair to conclude that further assessments of the utility of adjunctive tricyclic antidepressant medication among

substance-abusing

dysphoric

schizophrenic

patients

is

warranted.

Preliminary observations suggest that the best candidates for those trials would be

those

individuals

whose

psychotic

diathesis

is under

at

least

moderately good control with neuroleptic medication, and in whom an attempt has been made to rule out the confound of (even subtle) neuroleptic-induced akinesia.

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