30 SCHIZOPHRENIA BULLETIN Treatment of Schizoaffective Disorders · 2017-06-02 · 30 SCHIZOPHRENIA...

30 SCHIZOPHRENIA BULLETIN

Treatment ofSchizoaffective Disorders

by Paul J. Goodnickand Herbert Y. Meltzer

Abstract

Studies that compare the treatmentresponse of patients diagnosed asprimary affective disorder or schizo-affective disorder are reviewed.Although relatively few controlled oruncontrolled studies of thechemotherapy of schizoaffectivedisorders have been conducted,available evidence suggests that: (1)lithium carbonate is effective in theinitial treatment of both schizo-affective mania and mania; (2)antidepressants alone, neurolepticsalone, or their combination can beeffective in the initial treatment ofboth schizoaffective depression andprimary depression; and (3) prophy-lactic administration of lithiumcarbonate may reduce the frequencyand duration of relapse in bothschizoaffective manic and schizo-affective depressed patients. Thus,treatment studies indicate that theschizoaffective disorders are verysimilar to the primary affectivedisorders with regard to response topharmacologlc treatment. Evidencefrom this laboratory that schizo-affective manic patients respondmore slowly than manic patients tolithium or neuroleptic treatment ispresented.

The controversy as to whetherschizoaffective disorder is a subtypeof schizophrenia (AmericanPsychiatric Association 1968; Detreand Jarecki 1971), a form of primaryaffective illness (Pope and Lipinski1978), or a unique syndrome with aunique etiology, biological concom-itants, genetic predispositions, andtreatment outcome (AmericanPsychiatric Association 1980; Klein etal. 1981) has been reviewed in otherarticles in this issue from the vantagepoint of epidemiology, familyhistory, genetics, and biologicalstudies. Clinical response to somatic

treatment may also be of value inclarifying the relationship betweenthe major psychoses. For example, ithas been suggested that a good thera-peutic response to lithium or antide-pressant drug treatment may be acriterion for differentiation ofprimary affective illness from othertypes of psychiatric illness (Forssmanand Walinder 1970; Sicignano andLichtenstein 1978). Other investi-gators have discussed and usuallyrejected this possibility (Noack andTrautner 1951; Kingstone 1960;Wharton and Fieve 1966; Goodwin,Murphy, and Bunney 1969; Shopsin,Johnson, and Gershon 1971; Dunnerand Fieve 1978; Schou 1979; Bradenet al. 1982). Should establishedtherapies of affective disorders fail tobe of clinical value in the treatmentof schizoaffective depression, schizo-affective mania, or both, this wouldprovide some indication that thelatter are either not related toaffective disorders or that they are-very distinct subtypes of affectivedisorders with an important discon-tinuity in the area of treatmentresponse. However, prophylacticeffects of somatic treatment onaffective and schizoaffective disordersmight be more informative becauseof the greater likelihood that acommon etiological factor mighthave to be present for a prophylacticeffect to be manifest.

We will review studies whichcompare various effects of somatictreatment in schizoaffective andmajor affective disorders: (1) theeffectiveness of various drugtreatments in the initial treatment ofschizoaffective mania and depression;(2) prophylactic treatment of schizo-affective and primary affectivedisorders; (3) differences in drug

Reprint requests should be sent to Dr.P.J. Goodnick, Illinois State PsychiatricInstitute, 1601 W. Taylor St., Chicago. 1L60612.

VOL. 10, NO. 1, 1984 31

response between schizoaffective andprimary affective disorders; and (4)the relationship of various diagnosticcriteria for schizoaffective disorder todrug response. The treatment ofschizoaffective disorders with lithiumwas recently reviewed by Delva andLetemendia (1982) and Fieve andGoodnick (1983).

Initial Treatment ofSchizoaffective Mania

The initial treatment of schizo-affective mania and mania withlithium, neuroleptics, or the combi-nation has been intensivelyinvestigated. There are 14 publishedstudies other than case reports, sixdouble-blind and eight open, of theeffect of these drug treatments inschizoaffective mania. Table 1 listseach of these studies, along with adescription of the subjects, diagnosticcriteria, response measures, drugsand dosages, duration of treatment,and an overall summary of theclinical outcome.

Several problems complicate theinterpretation of these studies.Firstly, before the development of theresearch diagnostic criteria (RDC) bySpitzer, Endicott, and Robins (1978),there was even greater ambiguity andvariation in the diagnostic criteria forall three diagnostic categories thancurrently exists. Some studiesinitially included schizoaffectivepatients with schizophrenic patientsand only later considered bothgroups separately. This raises thepossibility that the schizoaffectivepatients included were those whosesymptomatology was closer toschizophrenia than to affectiveillness. Studies designed to contrastthe response of schizoaffective witheither primary affective disorder orschizophrenia are more likely toproduce reliable comparisons.Secondly, many studies (Rice 1956;

Wharton and Fieve 1966; Gottfries1968; Aronoff and Epstein 1970;Megrabyan et al. 1979; Pope et al.1980) did not apply rating scales to ^measure clinical change. However,we have opted to include their resultsin this review when we consider theglobal assessments of all studies.Finally, in all but two studies,treatment periods were 1 month orless which may be inadequate toassess clinical efficacy (see below).

Despite the difficulties cited above,surprising agreement in the results isevident. First, the mean rate of atleast partial response to lithiumcarbonate treatment in schizo-affective mania in all 14 studies(76.5 ± 18.2 percent, n = 290) issimilar to that in manic patients(93 ±7.7 percent, n = 463). Theonly study (Pope et al. 1980) thatdirectly compared lithium respon-siveness in mania and schizoaffectivemania diagnosed by RDC reported a95 percent rate of partialimprovement for schizoaffectivemania and 100 percent for mania.Three studies (Alexander, VanKammen, and Bunney 1979;Biederman, Lerner, and Belmaker1979; Carman, Bigelow, and Wyatt

1981) that used both the RDC criteriaand a double-blind research designfound the incidence of partialsymptom improvement in schizo-affective mania to vary from 60percent (Carman, Bigelow, andWyatt 1981) to 100 percent(Alexander, Van Kammen, andBunney 1979), but no manic patientswere included. The most recent suchstudy (Braden et al. 1982) found nodifferences among manic, schizoaffec-tive manic, and schizophrenicpatients (modified RDC) in finalglobal ratings following treatmentwith lithium or chlorpromazine.However, when overactive patientswere excluded, schizophrenic patientsdid more poorly on both drugs.

The proportion of schizoaffectivemanic patients who responded tolithium treatment (36-100 percent,n = 94) was higher than that inschizophrenics (0-40 percent,n — 113) in all investigations whichhave included both diagnostic groups(Rice 1956; Gottfries 1968; Small etal. 1975; Alexander, Van Kammen,and Bunney 1979; Hirschkowitz et al.1980; Pope et al. 1980; Carman,Bigelow, and Wyatt 1981). Four ofthese studies diagnosed patientsaccording to RDC; one (Hirschkowitzet al. 1980) was open and the otherthree (Small et al. 1975; Alexander,Van Kammen, and Bunney 1979;Carman, Bigelow, and Wyatt 1981)were double-blind. The open studyshowed only a slightly greater rate ofresponse in the schizoaffective manics(36 percent) than in the schizo-phrenics (25 percent); the double-blind studies demonstrated thatlithium was much more effective inthe schizoaffective manics (87 ± 23percent, n ~ 12) than in the schizo-phrenics (34 ± 14 percent, n = 30).

Extent of Treatment Response.Although the percentages of schizo-affective manic and manic patientswho show partial improvement inresponse to lithium are comparable,available evidence suggests thatschizoaffective manic patients are lesslikely than manic patients to achievenearly complete remission ofsymptoms in response to lithiumduring the period of observation(Rice 1956; Gottfries 1968; Zall,Therman, and Myers 1968; Aronoffand Epstein 1970; Johnson 1970;Pope et al. 1980). These studiesreported that marked improvementor total symptom elimination bylithium occurred in 73 ± 18 percent(n «= 167) of manic patients and26 ± 29 percent (n - 107) of schizo-affective patients. Two controlledstudies (Aronoff and Epstein 1970;

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Johnson 1970) reported manicpatients to have a significantly better

. response to lithium than schizo-affective patients: manic patients(n = 31), 71-79 percent remission;schizoaffective manic patients(n = 17), 9-33 percent remission.However, neither of these studiesused the RDC. All five studies thatdid not use the RDC reported thatonly a small proportion of schizo-affective manics had a nearly fullremission after lithium: mean15 ± 13 percent, range 9-33 percent(n •= 55). Only one (Pope et al.1980) of the six reports, an open oneusing retrospective analysis,employed the RDC. These investi-gators reported marked improvementafter lithium treatment in both manicpatients (92 percent) and schizo-affective patients (80 percent). Thus,a smaller proportion of schizo-affective manic patients diagnosed bycriteria other than the RDC show acomplete response to lithiumcompared to patients who meet theRDC for schizoaffective mania.

Response of Thought Disorder toLithium. An important considerationis the differential response ofparticular symptoms to lithiumtreatment in the schizoaffectivemanic patients. There have beenthree (Small et al. 1975; Biederman,Lerner, and Belmaker 1979; Carman,Bigelow, and Wyatt 1981) double-blind, placebo-controlledinvestigations of lithium carbonate inthe treatment of schizoaffectivemanic patients maintained on neuro-leprics, and one such study(Alexander, Van Kammen, andBunney 1979) in which lithium alonewas used. Three of these studies(Alexander, Van Kammen, andBunney 1979; Biederman, Lerner,and Belmaker 1979; Carman,Bigelow, and Wyatt 1981) used theRDC whereas the other (Small et al.

1975) used criteria devised by itsinvestigators. Biederman, Lerner, andBelmaker (1979) reported lithiummore effective than placebo inreducing ratings of conceptualdisorganization in RDC schizo-affective manic patients; Small et al.(1975) did not find this in schizo-affective manic patients. Alexander,Van Kammen, and Bunney (1979)and Carman, Bigelow, and Wyatt(1981) did not rate change in thoughtdisorder. Several open studies,including Rice (1956) and Zall,Therman, and Myers (1968), foundlithium was effective only in treatingaffective symptoms, in a highproportion of schizoaffective manicpatients. Lithium had a beneficialeffect on thought disorder in only0-10 percent of schizoaffective manicpatients.

Response of Hallucinations toLithium. Auditory hallucinationshave been reported to respond tolithium (Forssman and Walinder1970; Freedman and Schwab 1978;Braden and Quails 1979;Wagemaker, Lippmann, and Bryant1979). Two controlled studies haveused the Brief Psychiatric RatingScale (BPRS; Overall and Gorham1962) to evaluate changes in halluci-nations in schizoaffective manicpatients. The study that used RDCcriteria found lithium to have a slightadvantage over placebo (Biederman,Lerner, and Belmaker 1979); theother showed no difference (Small etal. 1975).

Response of Paranoia and Delusionsto Lithium. There are some data onthe effectiveness of lithium treatmentof paranoid delusions and unspecifiedpsychotic symptoms in schizo-affective manic patients. As withhallucinations, case reports showalmost total remission of these symp-toms in schizoaffective patients

treated with lithium alone (Forssmanand Walinder 1970; Freedman andSchwab 1978; Braden and Quails1979; Wagemaker, Lippmann, andBryant 1979). Alexander, VanKammen, and Bunney (1979) andCarman, Bigelow, and Wyatt (1981)reported results of double-blind,placebo-controlled studies whichfound significant improvement in"psychosis" in schizoaffective manics(RDC) after lithium therapy. Twofurther studies (Small et al. 1975;Biederman, Lerner, and Belmaker1979) that presented change in BPRSratings during lithium treatmentfound no significant change inunusual thinking but significantimprovement in suspiciousness.Biederman, Lerner, and Belmaker(1979) used the RDC, whereas Smallet al. (1975) used Feighner criteria fordefining mania but used their owncriteria to define schizoaffectivemania. In a study of schizoaffectivemanics diagnosed by the RDC(Biederman, Lerner, and Belmaker1979), lithium was significantly betterthan placebo on BPRS subscales.Thus, the three studies that appliedthe RDC for schizoaffective maniadescribed significant lithium-inducedimprovement in psychotic symptoms,whereas the one study that did notfound no response.

Comparison of Lithium andNeuroleptic Response. The relativeefficacy of lithium carbonate andneuroleptics, or their combination, inthe treatment of mania and schizo-affective mania has been examined inonly five studies (Shopsin, Kim, andGershon 1971; Johnson et al. 1971;Prien, Caffey, and Klett 1972a,1972k; Braden et al. 1982). Shopsin,Kim, and Gershon (1971) reportedthat chlorpromazine (CPZ) treatmentproduced greater improvement in 15BPRS items in a group of schizo-affective (n = 4) and schizophrenic

VOL. 10, NO. 1, 1984 35

(n = 17) patients than did lithium.These differences reached statisticalsignificance for the BPRS itemssomatic concern, grandiosity, andsuspiciousness. Johnson et al. (1971)reported the results of a single-blindtrial of CPZ or lithium in 21 manicand 13 schizoaffective manicpatients. Manic patients had anoverall favorable response to bothCPZ and lithium; CPZ was superioronly for the mannerisms scale.However, schizoaffective patientssignificantly responded to CPZ butnot to lithium. The two medicationsproduced equal improvement inpsychotic symptoms, i.e., conceptualdisorganization, suspiciousness,hallucinations, and unusual thoughts.Prien, Caffey, and Klett (1972a,1972b) reported results of theVeterans Administration-NationalInstitute of Mental Health collab-orative study of acute treatment ofmanic (n — 255) and schizoaffectivemanic illness (n = 83). Lithium andCPZ were equally effective in bothgroups overall, but CPZ producedmore rapid sedation in those patientsin both diagnostic groups who were"highly active." Furthermore, in the"highly active" schizoaffectivesubgroup, CPZ produced greaterbenefit than lithium in BPRSconceptual disorganization, suspi-ciousness, and hallucinatorybehavior. Pope et al. (1980), in theonly study using RDC, reportedmoderate improvement or better inmanic patients following eitherlithium alone or lithium plus neuro-leptic in all 30 patients studied. Sucha response was found in two of threemanic patients receiving neurolepticalone. The comparative effectivenessof drug treatments in schizoaffectivepatients was as follows: lithiumalone (95 percent, n = 20), lithiumplus neuroleptic (86 percent,n " 14), and neuroleptic alone (83percent, n = 12). Here, as before.

when schizoaffective patients werediagnosed by specific criteria, theirresponse was similar to that foundfor manic patients, i.e., there is littledifference in therapeutic effectbetween lithium alone, neurolepticalone, or lithium plus neuroleptic.Braden et al. (1982) also found thataside from an initial advantage forchlorpromazine over lithium inoveractive patients, lithium andchlorpromazine produced similarclinical improvement.

Latency to Response inSchizoaffectives and Manic-Depressives. There is some evidenceto suggest that manic patientsrespond more rapidly to lithium thando schizoaffective manic patients.The two studies showing the greatestdiscrepancy in response rates tolithium between manic andschizoaffective manic patients hadthe shortest treatment periods.Aronoff and Epstein (1970), withonly 2 weeks of treatment, reported100 percent of 12 manic patients butonly 67 percent of 6 schizoaffectivemanic patients responded; Johnson(1970), with a 3-week duration oftherapy, found improvement in 95percent of 19 manic but only 45percent of 11 schizoaffective manicpatients. Of the more recent studies,the one with the lowest rate ofresponse to lithium in schizoaffectivemanic patients (36 percent) used onlya 2-week period of drug adminis-tration (Hirschkowitz et al. 1980). Ofthe 10 studies indicating duration oftreatment (table 1), the meanproportion of schizoaffective manicpatients showing improvement in thefive studies with a treatment durationof > 4 weeks was 85 ± 9 percent(n = 56). The five studies with atreatment period of < 3 weeksreported a lower percentage ofresponse, 52 ± 34 percent (n = 41).These rates were nearly significantly

different (t •=• 2.13, df - 8, p < .10).The correlation between treatmentweeks and percentage of schizo-affective patients responding(r - 0.62, df = 8, p < .10) was alsonearly significant.

A Study of Rate and Extent ofSymptom Response In Manics andSchizoaffectives. Some of thequestions concerning symptomimprovement and rate of response inmania and schizoaffective maniahave been considered in a recentlycompleted study from this laboratory(Goodnkk and Meltzer 1983).Preliminary results will be reportedhere. Seventy-one patients,subdivided into both major (mania,n — 41, and schizoaffective mania,n — 30) and minor (mania:psychotic, n = 23, and nonpsy-chotic, n = 18; schizoaffectivemania: mostly affective, n = 17, andmostly schizophrenic, n = 13)categories, were diagnosed accordingto the RDC, and by the presence orabsence of delusions, hallucinations,or both. The dose of lithium was1,500-1,800 mg/day in both diag-nostic groups, regardless of whetherneuroleptic drugs were also admin-istered. The peak daily dose ofneuroleptic in chlorpromazineequivalents was 1,200-1,400 mg/dayin both diagnostic groups, regardlessof whether lithium was also given.Of the 41 manic patients, 25 receivedlithium alone, 3 received neurolepticalone, and 13 received lithium plusneuroleptic. Of the 30 schizoaffectivepatients, 9 received lithium alone, 11neuroleptic alone, and 10 receivedlithium plus neuroleptic. This distri-bution was significantly different(chi-square •= 11.08, p - 0.004).The patients were evaluated by atrained clinical psychologist with twoinstruments: the BPRS completed atadmission and discharge/ and theSchedule for Affective Disorders and


Schizophrenia-Change (SADS-C;Endicott and Spitzer 1978) completedweekly. Furthermore, the GlobalAdjustment Scale (GAS) from theSADS-C was evaluated to identifythe week in which each patientreached 80 percent of maximalimprovement. Comparisons werethen made between diagnostic groupswith regard to: (1) change inSADS-C and BPRS subscale andtotal scores; (2) mean number ofweeks until 80 percent of maximalimprovement was reached; and (3)response to particular treatmentregimens.

Symptom Response. Evaluation ofclinical response by diagnosis andtreatment showed no majordifferences between schizoaffectivemanic and manic patients withregard to changes in GAS or totalBPRS for all treatment (see table 2)or for the three types of treatments.An analysis of the response of

specific SADS-C and BPRS items isof interest with regard to the issue oflithium specificity for affectivesymptoms. First, as shown in table 2,both schizoaffective and manicpatients showed a good response,'with significant improvementobserved in both affective symptoms(SADS-C manic syndrome, delusionsof grandeur; BPRS grandiosity,excitement) and nonaffectivesymptoms (SADS-C delusions ofreference and persecution, thoughtdisorder; BPRS conceptual disorgan-ization, suspiciousness, halluci-nations). The only exception is theSADS-C rating for auditory halluci-nations for which the manic patientgroup did not show significantimprovement. This is most likely dueto the low baseline rating of thissymptom in those patients, sinceimprovement was clearly evident,from an initial mean score of 0.82 toa final of 0.08. The combination oflithium plus neuroleptic was superior

to lithium alone only in reducing thesuspiciousness score on the BPRS(F - 5.35, df - 2, p = .04). Therewas no drug X diagnosis interactionfor the suspiciousness item. Nodifferences among treatmentcategories were found for thoughtdisorder, hallucinations, or delusions.This indicates that lithium is effectivefor nonaffective symptoms, and thatthe three treatments are equally effec-tive in decreasing nonaffective symp-toms. The finding that psychoticsymptoms in the schizoaffectivemanic patients respond to lithiumagrees with those of Biederman,Lerner, and Belmaker (1979);Alexander, Van Kammen, andBunney (1979); and Carman,Bigelow, and Wyatt (1981). They arealso in accord with those of Pope etal. (1980), in that all RDC schizo-affective manic patients showedmarked improvement duringtreatment; GAS scores increased amean of 40.3 points (141 percent

Table 2. Changes in symptom ratings after treatment

SADS-CGASManic syndromeAuditory hallucinationsDelusions of reference & persecutionDelusions of grandeurThought disorderBPRS (scales 0-6)Total BPRSConceptual disorganizationGrandiositySuspiciousnessHallucinationsExcitement

Baseline

Schizoaffec-tive mania

(n = 30)

28.6 ±14.117.0 ± 12.92.57 ± 2.873.03 ± 2.123.37 ± 2.703.22 ± 3.32

29.3 ±11.43.03 ± 1.942.71 ± 2.072.34 ± 1.942.31 ± 2.012.31 ± 1.86

Bipolarmania

(n = 41)

32.8 ± 13.021.2 ± 8.80.82 ± 1.451.71 ± 2.041.97 ± 2.200.95 ± 1.63

21.3 ± 10.92.10 ± 1.553.10 ± 1.661.48 ± 1.681.10 ± 1.562.18 ± 1.68

After treatment

Schizoaffec-tive mania(n = 30)

68.9 ± 16.9 1

1.81 ± 3.95 '0.38 ± 1.18'0.28 ± 0.77 1

0.53 ± 1.19'0.47 ± 1.44'

7.6 ± 9.0 '0.35 ± 1.05'0.64 ± 1.23 '0.42 ± 0.96 1

0.13 ± 0.57 '0.42 ± 0.92 '

Bipolarmania

(n = 41)

72.1 ± 17.3'3.08 ± 6.13 '0.08 ± 0.350.32 ± 0.83 1

0.52 ± 1.47 '0.02 ± 0.16 '

5.4 ± 5.7 '0.10 ± 0.38 1

0.69 ± 1 . 3 6 '0.31 ± 0.69 1

0.13 ± 0.57 '0.44 ± 0.94 1

1 p < .005.

VOL. 10, NO. 1, 1984 37

greater than baseline), and totalBPRS scores decreased 21.7 points(74 percent less than baseline).

Rate of Response. A significantdifference in the duration oftreatment needed to reach 80 percentof maximal improvement was foundfor the two diagnostic groups.Overall, schizoaffective patientsrequired 61.6 ± 31.5 days to achievethis degree of improvement, whereasbipolar manic patients required only26.6 ± 18.9 days (p < .001). Thus,it took about twice as long for eachtreatment to achieve the same degreeof effectiveness in the schizoaffectivemanic patients compared to themanic patients.

Neurotoxidty. Johnson (1970) andShopsin, Johnson, and Gershon(1971) concluded that lithium wasmore likely to produce neurotoxicityin schizophrenic and schizoaffectivepatients than in manic patients. Westand Meltzer (1979) also concludedthat acute manic, schizophrenic, andschizoaffective patients were atgreater risk for lithium-inducedneurotoxicity than chronically illpatients. West (1982) suggested thatthe relevant issue for vulnerability toneurotoxicity was not the diagnosisof schizophrenia or schizoaffectivedisorder, but rather duration ofillness; acutely ill patients are morelikely to become neurotoxic duringlithium treatment than chronically illpatients.

Conclusion. In conclusion, lithiumappears to be equally effective in theacute treatment of schizoaffectivemanic and manic patients diagnosedaccording to the RDC. Lithium aloneand neuroleptics alone producecomparable overall improvement andare effective in the treatment ofnonaffective and affective symptomsin both schizoaffective manic and

manic patients. Those studies whichhave reported that neuroleptics aremore effective than lithium in thetreatment of schizoaffective patientshave used criteria other than theRDC. Schizoaffective patients werefound to require a significantlylonger period of drug administrationthan manic patients to achievecomparable remission. Both disordersresponded to treatment with lithium,neuroleptics, and combinedtreatment. Thus, consideration ofdata on treatment of schizoaffectivemania and mania suggests there is noreason to reject the hypothesis thatschizoaffective disorder, as definedby RDC, is a variant of bipolardisorder. However, the much longerperiod which schizoaffective patientsrequire to respond to medicationcompared to manic patients may berelated to important differences inseverity of illness or possiblyunderlying biology.

Initial Treatment ofSchizoaffective Depression

There are 12 published controlledstudies (eight double-blind and fouropen) concerning the efficacy ofpharmacotherapy in the treatment ofschizoaffective depression. Table 3provides a description of thesubjects, diagnostic criteria, responsemeasures, drugs and dosages,duration of treatment, and an overallsummary of the clinical outcome.

Interpretation of these results iscomplicated by the same factorsdiscussed above with reference to thedrug treatment studies of schizo-affective manic patients: problems indiagnosis, lack of application ofstandard measures of clinical change,and variability in treatment periods.

Antidepressant Response. Fourstudies (Angst 1961; Greenblatt,Grosser, and Wechsler 1962; Hordernet al. 1963; Avery and Winokur

1977) have compared the response ofmajor and schizoaffective depressionto antidepressants. The proportion ofpatients who showed improvementwere: bipolar depressives (54 ± 18percent, n = 64), unipolardepressives (59 ± 18 percent,n " 237), and schizoaffectivedepressives (54 ± 18 percent,n «« 49). Three studies that used theRDC—one retrospective (Avery andWinokur 1977), one double-blind(Brockington et al. 1978), and oneopen (Brockington, Kendell, andWainwright 1980)—report a low rateof response of schizoaffective patientsto antidepressant drugs (37 ± 8percent, n = 150). These results aregenerally supported by anotherdouble-blind study (Prusoff et al.1979) which evaluated the effect ofadding amitriptyline to neurolepticsin 40 depressed schizophrenics whowere diagnosed according toDSM-III, but who would probablymeet the RDC for schizoaffectivedepression. Little significantimprovement was found. Twoarticles (Greenblatt, Grosser, andWechsler 1962; Hordern et al. 1963)published data comparing psychoticdepression and schizoaffectivedepression. The rate of response ofschizoaffective depressed patients(23-50 percent, n = 35) was slightlylower than that of psychoticdepressed patients (30-67 percent,n — 33). These results for delusionaldepression are comparable to othermore recent reports (Glassman,Kantor, and Shostak 1975; Nelsonand Bowers 1978; Avery andLubriano 1979).

Neuroleptic Response. Brockingtonet al. (1978) and Brockington,Kendell, and Wainwright (1980)examined the effect of neurolepticsalone, or in combination with antide-pressants, in the acute treatment ofschizoaffective depression. The 1978

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report was based on a double-blindstudy including amitriptyline alone(150-200 mg), chlorpromazine alone(450-750 mg), and combinedtreatment. The proportion of patientswho recovered in response tochlorpromazine alone was greaterthan the proportion who respondedto amitriptyline. The combination ofdrugs produced partial improvementin a higher proportion of patientsthan either individual treatment (75percent combined, 54 percent chlor-promazine alone, and 46 percentamitriptyline alone). In an openstudy, Brockington, Kendell, andWainwright (1980) also reported thatneuroleptic alone was superior totricyclic antidepressant alone: 55percent of neuroleptic-treated patientsimproved compared to 33 percent oftricyclic antidepressant-treatedpatients.

Lithium Response. Five studies(Small et al. 1975; Alexander, VanKammen, and Bunney 1979; VanKammen, Alexander, and Bunney1980; Hirschkowitz et al. 1980;Carman, Bigelow, and Wyatt 1981)have examined the response ofschizoaffective depressed patients tolithium carbonate. Lithium appearsto have comparable modest efficacyfor both schizoaffective depressionand some forms of schizophrenia. Allbut one of these studies (Small et al.1975) applied RDC. All but one(Hirschkowitz et al. 1980) weredouble-blind. It should be noted thatHirschkowitz et al. (1980) did notseparately describe the clinicalresponse of schizoaffective manic andschizoaffective depressed patients tolithium; therefore, it is not possibleto evaluate fully the results of thisstudy. The proportion of schizo-phrenic and schizoaffective patientswho responded to lithium in theother four reports was 36 ± 8percent (n — 5) and 38 ± 10 percent

(n = 30), respectively. VanKammen, Alexander, and Bunney(1980) reported that 6/10 (60 percent)of schizoaffective depressed patientsreceiving lithium had a reduction ofat least 1.5 on the depression ratingon the Bunney-Hamburg scale.

Electroshock Response. Seven reports(Greenblatt, Grosser, and Wechsler1962; Hordern et al. 1963; Folstein,Folstein, and McHugh 1973; Wells1973; Avery and Winokur 1977;Brockington, Kendell, andWainwright 1980; Ries et al. 1981)present data on the efficacy ofelectroconvulsive therapy (ECT) inthe treatment of schizoaffectivedepression. Two of these (Greenblatt,Grosser, and Wechsler 1962; Averyand Winokur 1977) compared theefficacy of ECT in schizoaffectivedepression and major depression.Both studies demonstrated similarrates of response in bipolardepression (43-80 percent, n = 19),unipolar depression (52-89 percent,n °= 132), and schizoaffectivedepression (41-80 percent, n = 27).Two studies that did not use theRDC (Greenblatt, Grosser, andWechsler 1962; Hordern et al. 1963)report a higher rate of response toECT in schizoaffective depression(80-100 percent) than do studies thatused the RDC (Avery and Winokur1977; Brockington, Kendell, andWainwright 1980) (41-62 percent).These four studies report that ECT ismore effective than pharmacotherapyin the treatment of schizoaffectivedepression. A similar conclusion hasbeen reached with regard topsychotic depression. Overall,54 ± 12 percent (n =• 56) markedlyimproved following ECT, but only30 ±6 percent (n - 75) after antide-pressants. Three studies (Folstein,Folstein, and McHugh 1973; Wells1973; Ries et al. 1981) noted thatschizoaffective patients responded

better to ECT than did schizo-phrenics, and that the response ratein the schizoaffectives was compara-ble to that usually reported in affec-tive patients.

Thus, the response to drugtreatment and ECT of schizoaffectivedepressed patients is not significantlydifferent from that of majordepression, very close to that foundin delusional depression, butsignificantly better than that ofschizophrenics. ECT is superior toantidepressant drugs but, even then,the maximal percentage of RDCschizoaffective depressed patientsresponding is approximately 50percent. Few schizoaffectivedepressed patients respond to eitherantidepressant alone or lithiumalone.

A Study of Symptom Response inSchizoaffective Depression. Thecomparative effectiveness of drugtreatment of schizoaffectivedepression and major depression onspecific symptoms was considered ina retrospective analysis from thiscenter. Fifty-six patients with majordepressive disorder and 44 patientswith schizoaffective depression,diagnosed according to the RDC,were included in an analysis ofsymptom change during the course oftreatment with neuroleptics orantidepressants. A criterion forinclusion in this analysis was apretreatment GAS rating from theSADS of 60 or below. A furtherrequirement was a 3-week treatmentperiod with a neuroleptic at a dose ofat least 600 mg equivalent of chlor-promazine or 150 mg imipramine,desipramine, amitriptyline, ormaprotiline, of 75 mg of nortrip-tyline, and of 300 mg of trazodone.The patients were evaluated weeklyby a trained psychologist with theSADS-C. Symptom response wasmeasured by change in the GAS,

VOL. 10, NO. 1, 1984 41

depressive syndrome, auditory hallu-cinations, delusions of reference andpersecution, and thought disorder;all of these are subscales of theSADS-C. Furthermore, a computer-generated Hamilton depression totalbased upon the SADS-C was alsoused for outcome measurement.

Analysis of outcome (table 4)yielded few differences in responsebetween diagnostic groups. Schizo-affective depressed patients hadgreater improvement than depressedpatients in auditory hallucinations(F = 8.55, df - 1, p = .004), butthe greater improvement was due togreater baseline severity (F — 23.07,df - 1, p - .0001). However, thepatients showing the greatestimprovement in the Hamiltondepression score derived from theSADS were the depressed patientstreated with antidepressants(F - 3.76, df - 1, p = .05).

Examination of the rating changefor each scale by diagnostic groupand treatment condition revealedother important differences (table 4).In the depressed group, there was aclear difference in the effect of the

treatment on specific symptoms.Thus, total Hamilton and SADSdepressive syndrome scores improvedafter antidepressants but not antipsy-chotics; auditory hallucinations, anddelusions of reference and perse-cution improved with neuroleptictreatment but not with antidepressanttreatment. In the schizoaffectivedepressed group, antipsychoticsproduced slightly more improvementthan antidepressants in GAS,auditory hallucinations, anddelusions of reference and perse-cution scores. Neuroleptics producedsignificant improvement in totalHamilton score in schizoaffectivedepressed patients, but antidepressanttherapy led to no significant changes.

These results are in agreement withprevious findings. Angst (1961);Greenblatt, Grosser, and Wechsler(1962); and Hordern et al. (1963)reported schizoaffective depressedpatients had a slightly poorerresponse to antidepressants than diddepressed patients, while Avery andWinokur (1977) found no significantdifference between the two groups(RDC criteria). Our finding that

depressed patients treated withantidepressants did slightly betterthan those treated with neuroleptictreatment are in accord with theabove. Furthermore, our finding thatneuroleptic treatment producessomewhat better results than antide-pressants in schizoaffective depressedpatients agrees with that of Brock-ington et al. (1978, 1980), whoshowed that chlorpromazine morefrequently produced improvementthan amitriptyline; 54-55 percent ofschizoaffective depressed patientsresponded to chlorpromazine andonly 33-46 percent responded toamitriptyline.

Prophylaxis of SchizoaffectiveDisorders

Ten studies have addressed theprevention of recurrences of schizo-affective illness, whether manic ordepressed type. Table 5 lists eachstudy, along with subject description,diagnostic criteria, responsemeasures, dose and duration ofadministered medication, experi-mental conditions, and results.

Table 4. Change in rating scale scores in schizoaffective depression and depression followingneuroleptic or antidepressant treatment

Schizoaffective depression Depression

Symptom

Global assessment

Hamilton total

Depression syndrome

Auditory hallucinations

Delusions of reference& persecution

Thought disorder

Neuroleptics

23.6 ± 19.8(.0001)'

5.8 ± 12.1(.0245)8.2 ± 16.7

(.0220)1.4 ± 2.4

(.0087)1.4 ± 2.4

(.0083)0.4 ± 1.4

(NS)

Anti-depressants

14.1 ± 17.7(.0027)

2.8 ± 10.1(NS)

7.9 ± 13.5(.0200)

2.2 ± 3.4(.0118)

1.3 ± 2.2(.0239)

0.3 ± 1.8(NS)

Neuroleptics

23.4 ±(.0001)3.0 ±

(NS)4.4 ±

(NS)0.6 ±

(.0552)1.3 ±

(.0200)0.1 ±

(NS)

21.8

10.9

15.5

1.2

1.9

1.2

Anti-depressants

21.0 ±(.0001)9.4 ±

(.0001)14.7 ±(.0001)

0.2 ±(NS)0.1 ±

(NS)0.1 ±

(NS)

10.2

11.3

16.0

1.4

1.2

0.8

1 Probability (In parentheses), paired t test, by diagnosis and drug treatment, for final vs. Initial state.

Tab

le 5

. P

rop

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acti

c tr

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of s

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ts

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net

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(197

0)

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noff

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in (1

970)

Ang

stet

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(197

0)

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tt(1

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197

4)

46 M

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58 R

D72

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192

MD

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M-I

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ayer

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ss

Aut

hors

Aut

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lad

mis

sion

Cha

nge

Intre

atm

ent

IMP

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KA

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Lith

ium

Lith

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Lith

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Lith

ium

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cebo

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now

n

Min

imum

bloo

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0.6

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3 ye

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% A

t le

ast

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oder

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% W

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ased

freq

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epis

odes

MD

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et a

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974)

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(197

5)

50 M

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9 M

47 M

D36

RD

3SA

WH

OD

SM

-II

Aut

hors

'

Aut

hors

'

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lad

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me

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l

Lith

ium

Pla

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0.6-

0.8

mE

q/l

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vel

1-3

year

s

18-7

5 m

onth

s

Ope

n

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88S

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% R

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ring

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men

tM

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19

SA

33

Per

rls (197

8)

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ss &

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g (1

979)

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21 M

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hor's

(sim

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to D

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ars

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MD

: 2.

8 ±

1.8y

ear3

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: 2.

4 ±

1.4

year

s

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n

% R

educ

tion

afte

rtre

atm

ent

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sode

s 76

Mon

ths

hosp

ltall-

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n 90

% R

educ

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laps

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69

CO O I Isl o -0 I 3J m zCD 3 z

VOL. 10, NO. 1, 1984 43

co co 2 CO

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The 10 studies compare results on220 schizoaffective patients,diagnosed according to variousdiagnostic criteria, with that of 574manic-depressive and 148 patientswith recurrent depression. Only 1 ofthe 10 studies was double-blind; itincluded only six schizoaffectivesubjects. All 10 studies used lithiumcarbonate for prophylaxis.

Some of the earlier studies report abetter response in bipolar patients(67-72 percent, n = 365) than inschizoaffective manic patients (40-53percent, n = 97) (Angst et al. 1970;Hofmann et al. 1970; Prien, Caffey,and Klett 1973, 1974). The finding ofAngst et al. (1970) that lithiumsignificantly reduced the frequency ofepisodes in schizoaffective patientsand the report of Prien, Caffey, andKlett (1973, 1974) that the relapserate of schizoaffective patientsincreased to 60 percent after the dis-continuation of lithium stronglyindicate that lithium was exerting aprophylactic action, even in theabsence of a placebo control. Recentstudies, which have had equalnumbers of subjects in eachdiagnostic group and clearly definedcriteria for diagnosis, have reportedmore equivalent efficacy in bothdiagnostic groups than the earlierones. Thus, the studies of Rosenthalet al. (1980) and Sarantidis andWaters (1981), which used the RDC,found that schizoaffective patients re-mained as well on lithium as didmanic patients. Rosenthal et al.(1980) compared the probability ofnonrelapse in manic and schizo-affective manic patients at weeks 16,52, and 104 of lithium treatment.After 1 year of treatment, schizo-affective patients were 13 percentmore likely to be in remission thanmanic patients; after 2 years, schizo-affective patients were 6 percent lesslikely than manic patients to still bein remission. Sarantidis and Waters

(1981) used length of hospitalizationas the criterion for lithium response.The proportion of patients having atleast a fair lithium response wasslightly greater in schizoaffectivemanic patients (89 percent) than inmanic patients (78 percent). Thedecrease in days spent in the hospitalcompared to the year beforebeginning prophylaxis with lithiumwas 62 percent for the manic patientsand 76 percent for the schizoaffectivepatients.

Thus, lithium carbonate,administered at the usual dosesneeded to achieve a plasmaconcentration of 0.6-1.0 mEq/1,appears to be effective in preventingrecurrences of schizoaffectivedisorder in up to 90 percent ofpatients.

Somatic Treatments ofSchizoaffective DisordersOther than Lithium,Neuroleptlcs, andConventional Antidepressants

Apomorphine and Bromocriptine.Dopamine agonists in low doses havebeen administered to psychoticpatients on the premise that stimu-lation of dopamine autoreceptors caninhibit the synthesis and release ofdopamine (Meltzer 1982). Recentstudies (Corsini et al. 1981; Meltzeret al. 1983) have suggested that lowdose dopamine agonist treatmentmay be more effective in the treat-ment of schizoaffective patients thanschizophrenics. Corsini et al. (1981)administered 1 mg of apomorphineintramuscularly to 36 patients orig-inally diagnosed as schizophrenic.Eighteen of these patients showedeither improvement of at least 75percent in baseline Brief PsychiatricRating Scale (BPRS) scores(responders) or no improvement(nonresponders). Diagnosis of thesepatients according to the RDC


indicated that seven of the nineresponders fulfilled criteria forschizoaffective disorder, manic type.Only one of the nine nonresponderswas schizoaffective (depressed type).

. Meltzeretal. (1983) administeredbromocriptine (0.5-6.0 mg/day) toseven schizophrenic and two schizo-affective patients after a 2-4 weekplacebo period. One of the schizo-affective patients showed markedimprovement and the othermoderate, as contrasted to mildimprovement in three of the sevenschizophrenic patients. The otherfour worsened following initialmodest improvement. The schizo-affective depressed patient whoresponded best demonstrated markedimprovement in both affective andpsychotic symptoms on 0.25-0.50mg/day for 3 weeks; a drug responsewas suggested by the relapse andrestoration of improvement when themedication was first withdrawn andthen reinstated.

Des-Tyr-y-Endorphln. The effect ofdes-tyrosine-y-endorphin (DTyE) hasbeen extensively investigated inschizophrenic and schizoaffectivepatients (Verhoeven et al. 1981;Meltzer et al. 1982; Van Praag et al.1982). Verhoeven et al. (1981) andVan Praag et al. (1982) administeredDTyE in doses of 1 mg intramus-cularly for 8-10 days. Nine of 23patients had a slight to moderateresponse; a marked response wasobserved in seven. All patients werealso being treated with neurolepticswhich had not been effective bythemselves. The schizoaffectivepatients (n •» 4) responded consid-erably less well than the chronicschizophrenic patients. Meltzer et al.(1982) conducted an open study ofDTyE in which the drug was admin-istered for 12 days in doses rangingfrom 1 to 10 mg/day. The studygroup included seven schizophrenicpatients and one schizoaffective

manic—mostly schizophrenic patientaccording to RDC. As in theprevious study, the schizoaffectivepatient did much less well than theschizophrenic patients. Threeinstances of moderate or markedimprovement and three of minimalimprovement were found in the sevenschizophrenic patients. There are nodata available on the effect of DTyEin patients with RDC diagnoses ofmajor affective disorder. The datafor the effectiveness of DTyE inschizophrenia and its ineffectivenessin schizoaffective disorders are farfrom conclusive.

L-Tryptophan. The "permissive"hypothesis of affective disorders isbased upon a serotonin deficiencyleading to vulnerability to developeither mania or depression (Prange etal. 1973). For this reason, theserotonin precursor, L-tryptophan,has been used for both the treatmentand prevention of manic-depressivedisorder (Van Praag 1982). A recentstudy compared the clinical responseto L-tryptophan plus lithium versusplacebo plus lithium in manic andschizoaffective manic patients(Brewerton and Reus 1983). Adouble-blind placebo-controlled studywith a 21-day drug treatment periodwas conducted. The patient sampleincluded nine patients with adiagnosis of bipolar disorder andseven with a diagnosis of schizo-affective disorder, according toDSM-III. All patients had ManicState Rating Scale (Beigel, Murphy,and Bunney 1971) scores above 24 atbaseline. L-Tryptophan was adminis-tered in increasing doses over 6 daysto a maximum dose of 3 grams, threetimes per day, between meals.Overall, the patients of bothdiagnostic types who received L-tryptophan showed greaterimprovement on both the ManicState Rating Scale and the Brief

Psychiatric Rating Scale as comparedto those who received only lithium,but this was considered to be moreevident in the schizoaffectivepatients. However, the relativelyliberal use of as needed neurolepticmedication makes it difficult tointerpret this finding.

Bupropion. There is extensiveevidence that bupropion is aneffective antidepressant for unipolarand bipolar depression (Maxwell etal. 1981). It produces few sideeffects, and, of particular impor-tance, has not been noted to producean exacerbation of psychoticsymptoms. This possibility had beenanticipated because bupropion is aneffective inhibitor of dopamineuptake and has few other knownactions (Cooper, Hester, andMaxwell 1980). A recent investi-gation of the antidepressant action ofbupropion suggests a significantdifference between schizoaffectivepatients and those with major affec-tive disorder. Goode and Manning(1983) treated nine schizoaffectivedepressed patients (RDC) withbupropion alone at a dose of 750mg/day. Three of the patients expe-rienced severe exacerbations ofschizophrenic-type symptoms thatrequired their discontinuation fromthe study. The other six patients didnot do particularly well. Eleven otherpatients received bupropion plushaloperidol; five were judged veryimproved and four moderatelyimproved. If it can be confirmed thatbupropion alone may produce antide-pressant effects in major depressionwith psychotic symptoms, but isineffective in schizoaffectivedepression except for producing anexacerbation of schizophrenic-typesymptoms, this drug could become auseful tool for identifying biologicaldifferences between these types ofpatients.

VOL. 10, NO. 1, 1984 45

Summary

Based on our review of the literature,the following major conclusionsconcerning the chemotherapy ofschizoaffective disorders and affectivedisorders can be drawn:

• Lithium carbonate and neuro-leptics, alone or in combination,are effective treatments for maniaand schizoaffective mania andproduce improvement in mood aswell as psychotic symptoms.

• Schizoaffective manic patientsrequire a significantly longer timethan manics to respond to thesemedications. This may be anindication of a qualitative or aquantitative difference between thetwo types of disorders.

• Schizoaffective depressed patientsmay respond to either neurolepticsor antidepressants, or the combin-ation, but their course is much lesspredictable than that of patientswith major depressive disorder.

• Lithium 'carbonate is an effectiveprophylactic treatment of schizo-affective disorder, with results atleast as good as in bipolar affectiveillness. This result suggests thatthere is overlap in the etiology ofschizoaffective and affectivedisorders.

Despite the abundance of studieswe have reviewed, there is stillconsiderable need for further studieswhich include a large series ofsubjects diagnosed by RDC or othercriteria which provide for the differ-entiation of subtypes of schizo-affective disorder. Ideally, thesestudies should include manic, majordepression, and schizophrenicpatients as comparison groups anduse random assignment to treatmentif more than one treatment is to becompared. Carbamazepine or L-tryptophan, with or without lithium,which have been reported to have

some efficacy in the major affectivedisorders, could be useful agents toinclude in some such studies.Prophylactic studies with lithium,carbamazepine, L-tryptophan, 5-hydroxyrryptophan, or placebo witha large cohort of schizoaffectivedepressed and manic patients, studiedover a long period of time andcompared with pure bipolar patients,should identify patients who arenonresponders. The nonresponderswould represent a potential group ofsubjects for further study of thepossibility that some schizoaffectivepatients are more like schizophrenicsor are a unique psychosis.

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The Authors

Paul J. Goodnick, M.D., is AssistantProfessor of Psychiatry, and HerbertY. Meltzer, M.D., is Professor ofPsychiatry, Pritzker School ofMedicine, University of Chicago,Chicago, IL. Drs. Goodnick andMeltzer are also at the Illinois StatePsychiatric Institute.

Announcement The annual meeting of the AmericanPsychopathological Association willbe held March 1-3, 1984, at the St.Regis-Sheraton Hotel, New York,NY.

The theme of the meeting is"Controversies in Schizophrenia."

Articles from invited guests will bepresented in plenary sessions.

For further information, writeto: Nancy C. Andreasen, M.D.,Secretary, Department of Psychiatry,The University of Iowa, 500 NewtonRd., Iowa City, IA 52242.

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