medication effects: conceptual and methodological issues in schizophrenia research

Clintrni P+ology Rwru, Vol. 12. pp. 345-361, 1992

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Copyright 0 1992 Pergamon Press Ltd.

MEDICATION EFFECTS: CONCEPTUAL AND METHODOLOGICAL ISSUES

IN SCHIZOPHRENIA RESEARCH

jack 1. Blanchard

Medical College of Pennsylvania at the

Eastern Pennsylvania Psychiatric institute

john M. Neale

State University of New York at Stony Brook

ABSTRACT. The majority of schizophrenia research is conducted with patients medicated with

neuroleptics. This medication has powerful and widespread effects on various neurotransmitter systems.

A review of the cognitive and motor side effects of neuroleptics, as well as the cognitive side effects of

anticholinergic medication, leads to the conclusion that such side effects must be acknowledged as

potentially serious confounds. Strategies available to researchers to assess, control for, or avoid these

medication effects are discussed and their limitations noted. Finally, recent developments are discussed

that may afford researchers an opportunity to more readily obtain drug-free patients; also, recommenda-

tions are providedfor research conducted with medicated participants.

Since the establishment of the efficacy of neuroleptics in relieving psychotic symptoms,

and their nearly universal clinical application since the mid-1950s researchers have had

to face the problems that arise from conducting investigations with medicated patients.

Concerned investigators have long since sounded warnings about the use of medicated

patients in research (e.g., Chapman & Chapman, 1973a). The subsequent accumulation

of research findings has served only to confirm the caution (if not alarm) raised by these

earlier writings. Yet, despite the compelling nature of this issue, one remains hard-

pressed to find studies conducted with drug-free patients. This paper will provide a

discussion of the conceptual and methodological problems associated with medication

effects in schizophrenia research. Although schizophrenia research will be the focus,

many of the issues addressed will also be germane to research with patients in other

diagnostic categories.

Correspondence should be addressed to Jack J. Blanchard, Department of Psychiatry, Medical College of Pennsylvania at EPPI, 3200 Henry Avenue, Philadelphia, PA 19129.

345

346 J. J. Blanchard and J. M. Neale

We will first briefly review the literature pertinent to the cognitive side effects of neuroleptics (see more detailed reviews by Heaton & Crowley, 1981; Medalia, Gold, & Merriam, 1988; Spohn & Strauss, 1989); however, our primary purpose is to identify and discuss broader research issues that have emerged from the work in this area. The behavioral or motor side effects of neuroleptics will be discussed with relevance to the study of symptomatology in schizophrenia. Recent studies evaluating the cognitive impairment that may be associated with anticholinergic medication- given to attenuate the motor side effects of neuroleptics-will also be reviewed. Following this discussion of medication effects, the research strategies available to study, control for, or avoid them will be evaluated.

COGNITIVE SIDE EFFECTS OF NEUROLEPTICS

The mechanism by which neuroleptics exert their therapeutic action appears to be in their ability to block dopamine receptors, especially D-2 receptors (Creese, 1983; Snyder, 1981). However, while dopaminergic blockade may be the primary mechanism of therapeutic action, other transmitter systems are impinged upon as well. Antipsychotic medications have variable antagonistic interactions with muscarinic, alpha-adrenergic, hista- minergic, and serotonergic receptors in the brain and peripheral tissues (Cohen, 1988; Enna & Coyle, 1983). Indeed, it has been recently argued that these other transmitter systems may play a nontrivial role in the therapeutic action of neuroleptics (Cohen, 1988).

Widespread changes in neurochemistry and the resultant clinical improvements suggest that schizophrenics’ performance on cognitive tasks would be altered as well. However, researchers can turn to a small body of literature that suggests that cognitive and percep- tual tests may be relatively unaffected by antipsychotic medication (e.g., Killian, Holz- man, Davis, & Gibbons, 1984; Spohn, Lacoursiere, Thompson, & Coyne, 1977). One interpretation of this literature is summarized by Heaton and Crowley’s (1981) review of the influence of somatic treatments on neuropsychological tests:

continuing administration of neuroleptic drugs to schizophrenic patients results in few

significant changes in neuropsychologicai test performance. There is, however, some consis- tency in reports indicating that the drugs enhance performance on attention tasks. Thus

once schizophrenics are stabilized on neuroleptic drugs, any drug-induced changes in neuropsychological test performance should (if anything) slightly decrease the likelihood of making

false diagnoses of brain damage. (p. 504)

While some may conclude from Heaton and Crowley’s (1981) summary that researchers need not be concerned with the effects of neuroleptics as confounds, a closer inspection of the literature indicates that such a conclusion may be overly optimistic. For instance, a more recent review of the neuropsychological literature (Medalia et al,, 1988) offers a more cautionary summary, concluding that some tests may be negatively affected while data on others are “highly equivocal” (p. 267).

Similarly, though Spohn and Strauss (1989) noted that neuroleptics result in improvements in such areas as thought disorder, sustained attention, and distractibility, they noted important limitations to this conclusion. The majority of studies investigating drug effects have utilized primarily chronic, hospitalized patients, thus potentially limiting the generalizability of the findings. Additionally, characteristics of such chronic populations (e.g., tardive dyskinesia) may have introduced confounds to this research. Spohn and Strauss (1989) further note that high doses of neuroleptics may have deleterious effects on measures that show improvement with lower doses. Finally, the lack of convergent

Medication Effects in Schizophrenia Research 347

validity of measures used in psychopathology research limits the extent to which investigators can assume that tasks purported to assess the same construct also share the same response to neuroleptics. Thus, it is premature to conclude that all cognitive tasks are impervious to the effects of neuroleptic medication for all schizophrenics.

Of course, in those cases where neuroleptics may indeed be found to enhance or normalize performance, the investigator must continue to be concerned about even this “benign” influence. This normalizing effect can obscure an important relationship between the test variable and diagnosis.

A final problem with the extant literature is its focus on neuroleptics and a lack of attention to other medications. Schizophrenics who do not respond adequately to neuroleptics may also be receiving a broad range of other medications (e.g., lithium carbonate, benzodiazepines), which may also represent possible confounds. Furthermore, it should be noted that schizophrenia studies frequently include other diagnostic groups (such as bipolar affective disorder) for purposes of comparison. These other patient groups are often receiving medications that may produce their own side effects. For instance, lithium carbonate has been shown to impair motor speed and long-term memory (Shaw, Stokes, Mann, & Manevitz, 1987) and to induce abnormal smooth-pursuit eye movements (Levy et al., 1985) in patients with bipolar affective disorder. Researchers must be wary of all drug effects in all patient groups studied.

MOTOR SIDE EFFECTS OF NEUROLEPTICS

In addition to the effects of neuroleptic medication on cognitive tasks, there are motor disturbances associated with the use of neuroleptics that may create confusion regarding the nature of a variety of symptoms. Given the movement in psychopathology research away from sole reliance on heterogenous diagnostic categories and toward symptom- based approaches (Neale, Oltmanns, & Harvey, 1985; Persons, 1986), the significance of these neuroleptic-induced motor side effects is especially acute. As researchers attempt to relate cognitive performance variables to a specific symptom (e.g., flat affect) or group of symptoms (e.g., the negative symptoms), it becomes increasingly important to eliminate the error variance associated with the measurement of these symptoms. One source of such error variance is the motor side effects (extrapyramidal symptoms) associated with neuroleptic medication.

Epidemiological data indicate that neuroleptic-induced extrapyramidal symptoms (EPS) are quite frequent. In a recent review (Ayd, 1983) based on 5,000 patients, 61.9% were found to have neuroleptic-induced EPS. It is interesting to note that these data reflect an increase over an earlier review (Ayd, 1961), which found an incidence of 38.9% in a survey of 1,825 patients. While this increase may be attributable to improved assessment measures, it is also possible that the higher incidence of EPS is a consequence of an increased use of high-potency neuroleptics. In the 1961 review (Ayd, 1961), 48.1% of the patients in the survey were receiving low-milligram, high-potency neuroleptics while in the more recent review (Ayd, 1983), all patients were being treated with such high-potency drugs.

Of the motor side effects, parkinsonian symptoms may be particularly problematic for the researcher as they can easily be confused with negative or vegetative signs (Casey & Keepers, 1988) and do not necessarily co-occur with the more readily identifiable spontaneous movement disorders (Van Putten & May, 1978). Akinesia has the earliest onset and is the most common of the parkinsonian side effects (Marsden, Tarsy, & Baldessarini, 1975). Symptoms of akinesia (also called bradykinesia) include “expressionless facies, loss of associated movements, slow initiation of motor activity, soft and monotonous speech”


(Marsden et al., 1975, p. 229). In a study of 94 newly admitted schizophrenics, Van

Putten and May (1978) found that following the start of drug treatment (mean = 26.1

days, SD = 17.3 days), 28 patients (30%) d eveloped akinesia without other EPS, 16

(17%) had akinesia in addition to other EPS, 18 (19%) developed EPS without akinesia,

and 32 (34%) were free of extrapyramidal symptoms. These data would suggest that

neuroleptic-induced parkinsonian symptoms are quite frequent in medicated patients.

Importantly, these symptoms may be misinterpreted as an expression of clinical symp-

tomatology such as depression (Rifkin, Quitkin, & Klein, 1975; Van Putten & May,

1978) or as flat affect (e.g., Mayer, Alpert, Stastny, Perlick, & Empfield, 1985; also see

Sommers, 1985, pp. 369-371).

The overlap between the phenotypic features of akinesia and flat affect is especially

striking. The defining features of flat affect, such as unchanging facial expression, de-

creased spontaneous movements, and lack of vocal intlexion (Andreasen, 1979), are all

subsumed by the features of akinesia outlined above. As acknowledged by Andreasen’s

(1984) Scale for the Assessment of Negative Symptoms (SANS), in assessing affective

flattening, “the rating of some items may be affected by drugs, since the parkinsonian

side effect of phenothiazines may lead to mask-like facies and diminished associated

movements” (p, 1). These shared features make it exceedingly difficult to disentangle

whether flat affect is a symptom or consequence of medication. Indeed, it was this concern

with distinguishing flat affect from neuroleptic-induced symptomatology that led Spitzer,

Endicott, and Robins (1978, p. 774) to exclude flat or inappropriate affect from their

Research Diagnostic Criteria (RDC).

ANTICHOLINERGIC DRUGS

Anticholinergic drugs are a primary method of treating neuroleptic-induced EPS. Based

on studies of normals (e.g., Drachrnan & Leavitt, 1974) demonstrating impairment in

memory functioning associated with anticholinergic drugs, some researchers (Calev,

1983; Frith, 1984) have warned that memory processes in schizophrenics may be im-

paired by anticholinergic medication. These drug-induced memory impairments are

problematic because they may be indistinguishable from the memory deficits thought to

be an aspect of schizophrenia itself (e.g., Calev, Venables, & Monk, 1983; see Neale &

Oltmanns, 1980, for a review of this literature).

Facilitated in part by the development of an assay for anticholinergic levels (Tune &

Coyle, 1980’), several studies have evaluated the relationship between memory impair-

ment and anticholinergic drugs in schizophrenics. These studies have employed a variety

of designs, including 1) comparing patients who are receiving neuroleptics with patients

receiving neuroleptics plus anticholinergic medication for EPS (Calev, 1984a; 198413); 2)

correlating anticholinergic serum levels with cognitive performance (Perlick, Statsny,

Katz, Mayer, & Mattis, 1986; Tune, Strauss, Lew, Breitlinger, & Coyle, 1982); 3)

within-subjects designs comparing performance while at higher anticholinergic serum

levels with performance obtained at lower anticholinergic levels (Strauss, Reynolds, Jay-

aram, & Tune, 1990); and 4) random assignment, crossover designs comparing anticho-

‘The radioreceptor assay developed by Tune and Coyle (1980) to determine serum anticholinergic levels measures anticholinergic activity based on competitive binding with the muscarinic receptor. Therefore, this method measures serum anticholinergic levels, and expresses these levels in atropine equivalents, regardless of the pharmacological source- whether from medication for the treatment of EPS or from neuroleptics (Tune, 1988; Tune 8r Coyle, 1980).


linergic and noncholinergic medications for the treatment of EPS (Fayen, Goldman,

Moulthrop, & Luchins, 1988; Hitri, Craft, Fallon, Sethi, & Sinha, 1987).

In the first investigation to employ an assay to determine serum anticholinergic levels,

Tune and associates (1982) found verbal recall to be significantly inversely correlated

with serum anticholinergic levels. Similarly, Strauss and colleagues (1990) demonstrated

impaired verbal recall at higher anticholinergic serum levels in a within-subject design.

In attempting to account for the adverse impact of anticholinergic drugs on recall tasks,

Calev (1983) has argued that they may impair the process of mnemonic organization.

Therefore, the fact that schizophrenics perform more poorly on recall than recognition

tasks is potentially accounted for by anticholinergic drug status.

Calev (1984b) tested this prediction using psychometrically matched recognition and

recall tasks with two groups of schizophrenics, one receiving neuroleptics and another

receiving neuroleptics as well as anticholinergic medication for EPS. Schizophrenics re-

ceiving anticholinergic drugs as well as neuroleptics performed worse than the group

receiving only neuroleptics on both tasks and performed worse on the recall than on the

recognition task. Patients receiving only neuroleptics did not show differential perfor-

mance on the two tasks. Calev (1984b) concluded that earlier findings of deficits in recall

but not recognition memory in schizophrenics may be accounted for by anticholinergic

medication. However, this conclusion should be tempered by the observation that the

patients receiving anticholinergic medication may have been more clinically impaired

than those receiving neuroleptics only (tending to have somewhat lower IQs, and to have

been hospitalized earlier, and for a longer period of time). Additionally, in another study,

Calev (1984a) failed to find differences in memory performance between patients on

neuroleptics and those receiving both neuroleptics and anticholinergic medication using

these same tasks. More importantly, however, since neuroleptics may have intrinsic

anticholinergic properties (see below), the comparison between patients receiving neuro-

leptics and those receiving both neuroleptics and anticholinergic drugs for EPS results in

findings which, while suggestive, are ultimately ambiguous.

Anticholinergic effects are not only associated with medication for the treatment of

EPS but may also result from the use of some neuroleptics. For example, the aliphatic

and piperidine phenothiazines have strong anticholinergic properties. Thus, anticholiner-

gic-induced cognitive impairment may result from neuroleptic medication alone. This

possibility is seen in a study by Perlick and colleagues (1986). Seventeen chronic inpatient

schizophrenics were tested for both verbal and nonverbal memory. While all of the

patients were receiving neuroleptic medication, only four (24%) were also taking anticho-

linergic drugs. The majority of patients (12; 71%) were receiving neuroleptics with

anticholinergic properties. Verbal recall was significantly inversely correlated with serum

anticholinergic levels; however, verbal recognition memory was unrelated to serum

levels. Serum anticholinergic levels were also unrelated to the visual, nonverbal, mem-

ory test. These findings suggest that anticholinergic drugs may affect only particular

types of memory (e.g., verbal) and may be more pronounced in recall than recognition

tasks.

While the studies described thus far indicate potential cognitive sequelae associated

with anticholinergic medication, these results are based upon correlational research in-

volving clinically determined medication types and dosages, which may limit the inter-

pretability of such findings. The presence of EPS requiring treatment, or higher levels of

anticholinergics, may simply reflect greater clinical impairment. One would be more

confident in the interpretation of data derived from research employing random assign-

ment to standardized medication regimens. Fortunately, two studies have utilized such a

design (Fayen et al., 1988; Hitri et al., 1987).

350 J. J. B&chard and J. M. Neale

In two studies of inpatient schizophrenics, Hitri and associates (1987) and Fayen and

colleagues (1988) compared the effects of two types of medication for the treatment of

EPS on memory: the usual anticholinergic medication (benztropine or trihexyphenidyl)

and a prodopaminergic medication (amantadine) that does not have anticholinergic prop-

erties. Hitri et al. (1987) found that the prodopaminergic medication did not alter perfor-

mance from baseline, EPS medication-free levels; however, while receiving anticholiner-

gic medication, patients showed significantly impaired verbal recall. Similarly, Fayen et

al. (1988) found verbal memory, particularly a measure of acquisition or learning, to be

significantly impaired in the anticholinergic condition compared to performance while in

the prodopaminergic phase. The positive results of these studies provide strong support

for the adverse effects of anticholinergic medication on memory.

The convergence of findings from studies conducted with normals (e.g., Drachman &

Leavitt, 1974; Van Putten et al., 1987) and schizophrenics, in both correlational and

experimental designs, points to the conclusion that anticholinergic drugs can impair

memory and thus must be of concern in research conducted with patients receiving such

medication. However, further research is required. The specificity of the induced mem-

ory impairment remains unclear. In the majority of studies reporting an effect of anticho-

linergic medication on memory in schizophrenics (Perlick et al., 1986; Tune et al., 1982;

Hitri et al., 1987) assessments were limited to verbal memory functioning utilizing a

word-list paradigm. In only one case (Perlick et al., 1986) was nonverbal memory as-

sessed, and it was found to be unaffected. Thus, studies should attempt to provide

broader assessments of memory functions to: (a) determine potential relationships be-

tween medication status and verbal as well as nonverbal memory, and (b) evaluate

the suggestion of Calev (1983, 1984b) that recall versus recognition memory may be

differentially vulnerable to the effects of anticholinergic medication. Furthermore, assess-

ments should be broadened to determine if other cognitive functions may be affected

(e.g., attention). Of course, in such studies it will be necessary to control for the psycho-

metric properties of the tasks employed so that differential performance is interpretable

as a differential deficit (Chapman & Chapman, 1973b). Additionally, as indicated by the

findings of Perlick and colleagues (1986), th e anticholinergic properties of some neurolep-

tics suggest the need to evaluate memory impairments related to these drugs in addition

to the drugs for the treatment of EPS. Finally, while difficult to conduct, investigations

should employ more stringent experimental designs utilizing random assignment to anti-

cholinergic or nonanticholinergic drug conditions (the availability of the prodopaminergic

EPS medication amantadine may allow the use of such designs without depriving patients

of needed medication while successfully manipulating anticholinergic exposure).

STRATEGIES FOR DEALING WITH MEDICATION EFFECTS

Faced with the difficulties imposed by possible medication effects, researchers have de-

vised a number of strategies to cope with the medication variable. These strategies include

statistical procedures that utilize drug-dose levels in analyses of performance, the use of

rating scales to control for motor side effects, the inclusion of naturally occurring subsam-

ples of drug-free patients in protocols, and the use of patients withdrawn from medication

for research purposes.

Dose Levels and Dependent Measures

Investigators may attempt to evaluate the contribution of drug status to observed perfor-

mance by determining the relationship between drug-dose level and the dependent vari-

able (e.g., Spohn, Coyne, Lacoursiere, Mazur, & Hayes, 1985). Since patients are


typically taking different neuroleptics, which may vary in their clinical potency, it is first necessary to translate dose levels into some equivalent standard for comparison. This is accomplished by transforming dose levels to chlorpromazine unit equivalents (CPUs) (e.g., Davis, 1974; Spohn et al., 1985; Spohn, Thetford, & Cancro, 1971). The investigator can then utilize CPUs in correlational analyses to determine the relationship between dose level and task performance. Typically, the investigator, having failed to demonstrate a correlation between dose level and performance, then argues that drug status cannot be considered a confound. This procedure is useful insofar as it provides descriptive information to the reader regarding the drug status of research participants (as called for by Spohn, 1973). However, this procedure does not successfully evaluate the potential confounding effects of medication.

As noted by Spohn (1973), the use of CPUs as a standard index of dose level is based only on the drugs’ clinical efficacy. Thus, while this index may equate the drugs for their ability to attenuate behavioral disturbance, they are not necessarily equated on other potentially important dimensions (such as their impact on various neurotransmitters). For example, as discussed above, it is known that neuroleptics differ in their anticholinergic properties. Recent findings indicate that these differences in anticholinergic effects can translate into differences in the degree to which dependent variables are impinged upon - for example, psychophysiological responsivity (Green, Nuechterlein, & Satz, 1989). Thus, the differential impact of various forms of neuroleptic medication on dependent measures may be obscured when dose levels are equated with transformation into CPUs.

A further problem with this strategy, as noted by Neale and Oltmanns (1980), arises if the effect of medication is to normalize performance on the dependent variable. Such a normalizing effect may result in a decrease in variability of performance. This reduced variability could make it difficult to demonstrate a relationship between drug status and performance though such a relationship may exist.

Two final difficulties with the use of dose levels in correlational analyses occur when significant correlations between dose level and performance are found. Given that dose levels are clinically determined, the degree of pathology may determine dose level, making the unambiguous interpretation of obtained correlations difficult. Furthermore, the usual next step in such a study is to “partial out” or covary the effects of drugs. However, this is widely regarded as a misuse of analysis of covariance (e.g., Lord, 1967, 1969; also see Cohen & Cohen, 1983, pp. 423-425, for an expanded discussion of the interpretive dilemmas faced when using this procedure).

In summary, the use of dose levels in correlational analyses to control for, or to evaluate the impact of, medication effects is inadequate. Conclusions based on such analyses are at least ambiguous and most likely misleading. The use of CPUs does, however, provide the research audience with basic information regarding patient characteristics and is helpful to the extent that it allows inferences pertaining to the clinical status of research participants.

Motor Side Effects and Rating Scales

As discussed above, the extrapyramidal side effects of neuroleptics, particularly akinesia, introduce difficulties in the assessment of symptoms such as flat affect. In rating flat affect, the psychopathology researcher will find no recommendations for dealing with this problem in Andreasen’s (1984) scale, as the only advice offered is that “the interviewer should be careful to note whether or not the patient is on medication, but should not try to ‘correct’ the rating accordingly” (p. 1).

Rating scales are available (e.g., Simpson & Angus, 1970; Simpson, Lee, Zoubok, &

3.52 J. I J. Blanchard and J. M. Neale

Gardos, 1979) to assess for medication-induced motor disturbances. In the rating of parkinsonian side effects (Simpson & Angus, 1970) symptoms such as stiffness, rigidity, and tremor are assessed (e.g., diminution in swing of the arms while walking, shuffling gait, stiffness and rigidity in shoulders, arms, and wrists, tremor in limbs). The assessment of tardive dyskinesia (Simpson et al., 1979) consists of the evaluation of abnormal persistent bucco-lingual-masticatory movements (e.g., puckering of the lips, sucking, chewing movements, tongue protrusion or tremor, grimacing) and abnormal movements of the limbs, trunk, and neck (e.g., purposeless, jerky movements and/or slow, rhythmic, writhing in fingers, wrists, and arms; stamping movements; twisting, undulant movements of trunk; head nodding).

One use of these motor side effect ratings is to employ them in statistical analyses in order to control for, or partial out, the contribution of these side effects to the obtained findings. Mayer and colleagues (Mayer et al., 1985) utilized such a strategy in studying flat affect in a medicated population of schizophrenics. Extrapyramidal symptoms (as assessed with a modified version of the Simpson & Angus, 1970, scale) emerged as one of four significant factors in their regression model predicting flat affect. Interestingly, this finding was obtained despite the use of anticholinergic medication within the patient sample.

While the use of rating scales to assess motor disturbances provides useful descriptive information about the population under study, their use in attempts to remove the variance due to motor disturbances is not without difficulty. First, as discussed with regard to dose levels, statistical control for the presence of EPS through such procedures as analysis of covariance is less than optimal. Second, the use of such scales assumes that all such motor disturbances are drug induced. However, such disturbances have been observed in never-medicated chronic schizophrenics (Cunningham Owens, Johnstone, & Frith, 1982; also see Marsden et al., 1975, for a review and discussion), suggesting that some motoric symptoms may be a feature of schizophrenia per se, thus leading to further confusion regarding whether one should attempt to control for them.

Third, akinesia may be present without the other EPS that these scales target (Rifkin et al., 1975; Van Putten & May, 1978). That is, since akinesia does not necessarily co-occur with gross motor abnormalities that are more clearly identified as being a mani- festation of EPS, scales for rating EPS may miss akinetic symptoms or misattribute them to medication-unrelated sources (depression or flat affect). Thus, it may be that the only way to assess if akinetic-like symptoms are truly drug-induced is to actually change the patient’s medication status. This could be accomplished by: 1) withdrawing the patient from neuroleptic medication and observing changes in these symptoms during the drug- free period (R&in et al.. 1975); 2) determining whether such symptoms reappear during readministration of neuroleptics after a period of drug withdrawal (Van Putten & May, 1978); or 3) evaluating the responsiveness of these symptoms to a trial of antiparkinsonian medication (R&in et al., 1975).

The Use of Drug-Free Patients

While the previously described strategies seek to control for or assess drug effects, the use of drug-free patients attempts to avoid drug effects entirely. Drug-free patients are used within one of two contexts. One exploits the availability of naturally occurring unmedicated patients (drug-naive patients, or perhaps unmedicated due to drug noncompliance or withdrawn based on clinical decisions) while the other removes patients from medication for research purposes.

The study of drug-naive patients circumvents confounds associated with a history of

Medicalion Effts in Schizophrenia Research 353

medication use (e.g., Farde et al., 1990; Wong et al., 1986). Drug-naive patients are, however, quite rare, since patients typically receive medication upon presentation to emergency rooms or through outpatient treatment prior to identification by the researcher. Additionally, drug-naive patients may have only a brief history of symptomatology, which may introduce ambiguities regarding diagnosis. Nonetheless, these patients represent a unique opportunity to study the phenomenon of schizophrenia without the concerns of drug effects.

There are two designs that have been referred to as designs of convenience (Spohn & Strauss, 1989) as they rely on the feasibility of testing naturally occurring drug-free patients. In the first design, unmedicated patients typically represent a subsample of the research group and provide an opportunity for the investigator to compare the performance of medicated and unmedicated patients. The rationale underlying such a comparison is that if differences between these two groups fail to emerge, it can be argued that drugs do not have an impact on performance. Alternatively, differences in performance are attributed to medication status. As pointed out by others as well (Chapman & Chap- man, 1973a), however, such conclusions are unjustified. Naturally occurring drug-free patients result from either clinical decisions based on symptomatic or diagnostic issues, or occur due to patient noncompliance with medication. Patients free of medication for these reasons may be either less disturbed or less responsive to medication. Such patient groups can thus be expected to represent an atypical population that differs from medicated patients on many variables.

The second design of convenience is a test-retest design. Naturally occurring unmedicated patients are tested while drug-free and then retested after drug treatment. This design may suffer from selection bias if drug-free status (e.g., noncompliance) is related to clinical or cognitive phenomenon; additionally, it lacks controls for practice and placebo-attention effects (Spohn & Strauss, 1989).

Patients removed from medication for research purposes provide a sample presumably free of the limitations associated with naturally occurring drug-free patients. The advantages offered by the use of these drug-free patients, and the disadvantages associated with other methods, have prompted some researchers (e.g., Chapman & Chapman, 1973a) to advocate conducting research only with such medication-withdrawn patients.

The simplest strategy requires the evaluation of patients following a drug-free period of a duration sufficient to achieve a washout of medication-usually 2 to 4 weeks for oral dosing. While this approach serves to eliminate the confound of medication effects, it may be faulted for treating such effects as a mere annoyance rather than as phenomena worthy of study.

An alternative approach acknowledges the utility of drug-free research while also seek- ing to understand the mechanisms of drug action (Neale & Oltmanns, 1980; Spohn, 1972). One design that has been employed to test for drug effects on schizophrenics’ performance is a test-retest design with: 1) a group of patients tested while off medication and then again while on, and 2) the use of a drug-treated group, also tested twice with an equivalent period occurring between testings, to control for practice effects. This design, however, fails to control for order effects and is typically not done under double-blind, or random-assignment conditions. Two designs described by Spohn and Strauss (1989) attempt to address these shortcomings.

In the counterbalanced crossover design, patients are randomly assigned (double-blind) to one of the two subgroups: One subgroup is tested while drug-free and then again while medicated, the second subgroup is first tested while medicated and then again when drug-free. Order effects are addressed with counterbalancing while the within-subject design controls for sample differences. An important requirement of this design is that


the drug-free and medication periods are sufficiently long to obtain the intended manipu-

lations in drug status (Spohn & Strauss, 1989). This issue, particularly duration of drug-

free status, is discussed more fully below.

In the independent-group, placebo-controlled design, all patients are initially discon-

tinued from medication for an adequate washout period and subsequently randomly

assigned (double-blind) to on-drug or placebo status. Patients are then evaluated over a

period of time of sufficient duration for the therapeutic effects of medication to emerge

(e.g., Spohn et al., 1977).

While the researcher encounters a number of logistical hurdles in going beyond the

simple assessment of patients withdrawn from medication and employing more rigorous

designs outlined above, the researcher also gains much from their use. As in the simpler

single test design, it is possible to evaluate performance and symptomatology presumably

free of drug side effects. Additionally, these designs provide the opportunity to examine

the mechanisms by which drugs exert their antipsychotic effects. As argued by Spohn

(1972):

rather than eliminate drug variance from studies of psychological deficit, it may be

highly instructive to examine directly the relationship between drug variance to psychological deficit in schizophrenia. I believe that the study of the interaction of antipsychotic drug effects with the psychological processes in which schizophrenic specific-deficit or deviance has been established-or sought-affords strategic opportunities for learning something

about what we have here called behavioral mechanisms of drug action and, indeed, about the nature of the mediating mechanisms of schizophrenic illness. (Spohn, 1972, p. 204)

One potential benefit of such research is to ascertain the sensitivity of tasks to the

effects of medication. It may be possible to identify tasks that are relatively impervious to

the effects of medication. These tasks could then be employed in future research with

more accessible medicated patients without undue concern regarding the confound of

medication status. However, this goal of generating a menu of tasks that are free of drug

effects is hampered by several concerns. First, the insensitivity of a particular task to one

neuroleptic does not necessarily allow for the prediction of that task’s insensitivity to

another type of neuroleptic. For example, as discussed above, neuroleptics may differ on

such dimensions as their anticholinergic properties. These anticholinergic properties may

be differentially related to various cognitive sequelae. Thus, one must be cautious in

generalizing results found with one class of neuroleptics to another. Additionally, while

performance on a particular task may be unaltered by medication, symptomatology

(e.g., thought disorder) is clearly changed, thus obscuring potential relationships between

cognitive performance and symptomatology. Finally, the limitations in the generalizabil-

ity of research findings in this area discussed above (Spohn & Strauss, 1989) further

complicate the task of identifying and employing tasks unaltered by medication status.

Sample Bias in Drug Withdrawal Research. While drug-free studies (regardless of the

design used) provide a powerful methodology for the study of cognitive processes and

symptomatology uncontaminated by drug side effects, there are issues that must be

considered when interpreting the results of such studies and in planning future research.

Aside from the ethical and logistical hurdles in withdrawing patients from medication,

there is the issue of subject attrition and the potential biasing of the final sample that may

result. The problem of subject attrition is demonstrated clearly in one of the most rigorous

drug-free studies done (Spohn et al., 1977). Of 63 patients initially taken off medication,


16 (25%) did not survive the initial 6-week washout period due to relapse, and another 7 were dropped during this period for “administrative reasons.” Thus, a total of 23 patients, or 37% of the initial sample, were dropped from the protocol by the 6th week of drug withdrawal. Following this 6-week drug-free period, 20 patients were randomly assigned to an 8-week placebo control condition and 20 to a drug-treatment group. Of the 20 patients in the placebo condition, 10 (50% of the placebo group) relapsed prior to the end of the 8-week period (5 relapsed during the first week of the placebo condition). Thus, by the end of this 14-week study, 26 patients or 41% of the original sample were dropped from the study due to relapse.

The loss of subjects due to relapse represents more than a simple inconvenience. The results obtained from surviving patients may be biased and of limited generalizability. In one study that evaluated such a possibility, Chapman (1963) screened a pool of 38 patients on at least one of two cognitive tests prior to discontinuation of medication. Of these 38 patients, 18 (47%) did not survive the 6-week drug-free period due to relapse. Analyses of the screening data indicated that those patients who did not survive the drug-free period had much greater pathology than those that did. Similar results were reported by Spohn and Fitzpatrick (1980) m an analysis of sources of sample bias in the Spohn et al. (1977) study discussed above. Spohn and Fitzpatrick (1980) found that “young, cognitively disorganized patients with impaired attention and psychomotor effi- ciency were more likely to relapse early in the course of withdrawal than older, cognitively and attentionally more intact patients” (p. 90). Th ese findings indicate that subjects able to survive drug withdrawal may be an unrepresentative and a less severely impaired patient group.

In addition to cognitive and demographic dimensions, selection procedures may also result in biased samples with respect to biological parameters. In order to evaluate this issue, Pfefferbaum, Zipursky, Lim, Zatz, Stahl, and Jernigan (1988) compared the com- puted tomographic (CT) results of patients who were able to participate in a 2-week drug withdrawal study (n = 23) with those patients from the same unit who were not withdrawn from medication (7~ = 22). The unmedicated group had significantly smaller cortical sulci (indicating less cortical atrophy) than the medicated group; there was also a nonsignificant trend for the unmedicated group to have smaller ventricles than the medicated group. As the authors concluded, “this finding suggests that patients who are able to discontinue medications may be a distinct subgroup of patients who differ on biological measures” (Pfefferbaum et al., 1988, p. 639) f rom those patients who are deemed unable to be removed from medication. This conclusion is constrained by the extent to which the decision process for inclusion in the drug withdrawal protocol was valid. Unfortu- nately, this decision process, while presumably based on some form of clinical evaluation, was not discussed in the article.

Biasing of patient samples may also be introduced before the protocol is actually conducted. Utilizing data from the Spohn et al. (1977) study, Spohn and Fitzpatrick (1980) offer a thorough and cogent assessment of the biases that can emerge during recruitment and informed-consent screening procedures. These authors found that medical staff decisions regarding the possible participation of patients (based on concerns pertaining to the risk of harm to the patient or to others) resulted in a biased selection of patients. Patients chosen by the medical staff to participate in the research protocol were marginally older, had a shorter duration of illness and hospitalization, and differed on dimensions of race (more blacks) and sex (fewer females) compared to patients whom the staff decided would not be eligible to participate. Of those patients the ward staff deemed eligible to participate, Spohn and Fitzpatrick (1980) f ound further differences between those patients consenting to participate and those refusing consent. The group of self-


consenting patients was younger, included more blacks, had been ill for a briefer period of time, had been hospitalized less time {but a greater proportion of the time), and had briefer hospitaIizations than those patients refusing to participate.

Given the biases that may be introduced by selection procedures and subject attrition, one may wonder at the viability of the drug-free design as a stratagem for avoiding the confounding effects of medication. Do such biases cripple attempts to generalize the findings based on drug-free patients to other patient populations? The confidence we can have in the generality of drug-free research findings will be a function of the degree to which variables that discriminate drug-free participants from nonparticipants, and patients who survive drug-free protocols from those who relapse, are related to the dependent variables under study (Spohn & Fitzpatrick, 1980).

Investigators conducting drug-free research should take care, then, to acquire information relevant to demographic, diagnostic, symptomatic, and cognitive functioning characteristics of the available patient sample. In this manner, differences between consenters and nonconsenters, as well as survivors and relapsers, can be evaluated to determine the extent to which the final research population deviates from the population of origin (as done by Spohn & Fitzpatrick, 1980). To the extent that discriminating variables do emerge, the investigator can determine the degree to which these variables are related to the dependent measures, and therefore determine the extent to which the generalizability of the results are compromised. As noted by Spohn and Fitzpatrick (1980), such a strategy does not protect against, or control for, the biases introduced by subject attrition due to relapse.

Long-Term Medication Effects. In addition to concerns regarding sampling procedures and subject attrition, there is an issue that is basic to the drug-withdrawal paradigm: To what degree are patients who are withdrawn from medication for several weeks truly free of drugs or drug effects? The elimination half-lives, with respect to plasma levels, of neuroleptics are typically reported to be 20 to 40 hours (Baldessarini, 1985), with the phenothiazines demonstrating a shorter half-life (lo-20 hours) than the butyrophenones (12-38 hours) (Mackay, 1980). These elimination half-life values would seem to support the current practice of using a 2- to 4-week drug-washout period prior to testing. How- ever, the interpretation of data relevant to plasma elimination must be tempered by several concerns.

The reported elimination half-lives may underestimate the persistence of neuroleptic activity. Plasma levels of neuroleptics do not reflect the concentrations of these drugs in the CNS. As summarized by Baldessarini (1985), “elimination from the plasma may be more rapid than from sites of high lipid content and binding, notably in the CNS. Direct pharmacokinetic studies on this issue are few and inconclusive” (p. 400). Recently, preliminary data from animal studies have demonstrated a significant behavioral persistence of haloperidol (Campbell & Baldessarini, 1985; Cohen, Babb, Campbell, & Baldes- sarini, 1988) that may be related to an extended half-life of disappearance from brain (16.7 days) (Cohen et al., 1988). These data are clearly provocative and await replication and further study in humans. However, these findings do warrant concern and, as Cohen et al. (1988) conclude, “the current common practice of studying patients in whom treatment with neuroleptic drugs has been discontinued for only a few days or weeks as equivalent to patients in a drug-naive state may well need to be reconsidered” (p. 880).

Additionally, the data regarding elimination half-lives are based on forms of administration other than repository preparations. Depot injection of neuroleptics results in a much longer elimination half-life (up to 10 days, Baldessarini, 1985) and can result in the maintenance of significant drug effects for several months following discontinuation of


administration (e.g., Wistedt, Wiles, & Kolakowska, 1981). Ayd (1983) reports that 14% of the 5,000 patients in his survey were receiving depot neuroleptics. The persistence of neuroleptic levels following the use of depot neuroleptics demands exclusion of patients receiving such preparations from typical drug-free protocols with washout periods of 2 to 4 weeks.

While the use of extended drug-withdrawal periods may assure adequate washout of medication, it does not, however, address the possibility of permanent drug-induced neurological alterations. Such enduring neurological side effects are most vividly demonstrated in the involuntary movement disorder of tardive dyskinesia (TD). While prevalence rates for TD vary as a function of patient characteristics and rating criteria employed, one conservative estimate (Casey & Keepers, 1988) reports that at least 15% to 20% of patients are afflicted. The time course for recovery from TD can be quite variable (Jeste, Potkin, Sinha, Feder, & Wyatt, 1979), b u may persist for years following discon- t tinuation of neuroleptic treatment (Penner & Marsden, 1983). Experimental animal mod- els of TD (e.g., Burt, Creese, & Snyder, 1977) suggest that it is a result of compensatory increases in the number of striatal dopamine receptors following chronic dopamine receptor blockade during neuroleptic treatment. Animal studies (e.g., Burt et al., 1977; also see Jenner & Marsden, 1983 for a review) indicate that these iatrogenic receptor alterations may be reversible following drug withdrawal; however, this conclusion is at odds with the persistence of TD in some psychiatric patients even after prolonged periods of drug withdrawal (Penner & Marsden, 1983). While the significance and prevalence of prolonged, perhaps irreversible, iatrogenic neurological changes awaits further study, these potential changes contribute to the interpretive difficulty faced by studies conducted with patients having a history of chronic neuroleptic use (despite being drug-free during experimental testing).

With the above considerations in mind, it should be noted that it is not the intent of the present discussion to invalidate the usefulness of drug-free studies. On the contrary, the evidence reviewed argues for the need to continue to utilize this design to avoid the potential confounding effects of medication status as well as to further delineate the mechanisms by which these drugs may act. However, the difficulties of drug-free research must be acknowledged to encourage researchers to develop methods to overcome these hurdles or, failing that, to acknowledge these limitations in the interpretation of empirical findings.

CONCLUSIONS AND RECOMMENDATIONS

The Future of Drug-Free Research

The most serious hurdle facing any proposal for withdrawing patients from medication for research is that such a procedure is unethical as it denies a treatment of proven efficacy. (For a recent example of such ethical objections see Chandler, 1989, and replies from Lieberman et al., 1989; also Neylan, Wright, Shelton, & van Kammen, 1990.) This concern certainly contributes to the reluctance of institutional review boards to approve, and of patients and their families to consent to participate in, such research. However, accumulating evidence regarding the incidence of neuroleptic-resistant patients (Brown & Herz, 1989) and the potential clinical usefulness of both very low dose (Kane, 1987) and intermittent medication schedules (Chiles, Sterchi, Hyde, & Herz, 1989) indicates that competent and ethical treatment need not follow a path of continued, uninterrupted neuroleptic use. The psychopathology researcher may find that as a consequence of these developments, more patients may be kept drug-free for periods of time.

358 J. J. Blanchard andJ. M. Neak

Failing to passively identify drug-free patients, researchers may find that the aforemen- tioned developments may make medical staff, patients, and their families more responsive to the suggestion of drug-withdrawal. In any case, as noted by a recent National Institute of Mental Health (NIMH) panel (Barchas et al., 1988), it is incumbent upon researchers to take an active role in creating environments conducive to drug-free research:

Clearly, there is a need to broaden the populations from which drug-free samples are drawn, but this will require greater tolerance for drug-withholding/withdra~al studies by members of Institutions Review Boards (IRBs), as well as patients and their families. Education of these individuals about potential gains from such studies could go a long way toward achiev-

ing greater tolerance of drug withholding; such education is within the purview of individual

investigators, who are most knowledgeable about local social values and mores, and who

have immediate substantive expertise. (Barchas et al., 1988, p. 446)

The Study of ~e~icdt~ Participd~ts

The realities of research with clinical populations will, however, continue to limit severely the availability of unmedicated research participants. What is to be done when research is conducted with medicated participants? Clearly, in such instances an adequate interpretation of the results needs to acknowledge the possible contribution of medication effects. Additionally, it is incumbent upon the researcher to provide full documentation of the medication status of participants whether or not the researcher suspects, or is concerned with, possible medication effects on the dependent variables under ,study (Spohn, 1973). Such information should include type of neuroleptics, dosage levels, as well as other medications, including anticholinergic drugs. The full report of drug status allows the investigator and the research audience to interpret the obtained results in the context of possible drug effects and to make inferences regarding the characteristics of the population under study (Spohn, 1973). If researchers conduct studies with participants receiving medications, they must fulfill their responsibility to adequately inform the scientific audience by providing a full report of medication status.

The use of rating scales for the measurement of motor side effects is also highly recommended. While these instruments do have their limitations (see above), they are useful in providing descriptive information regarding the population under study. Fur- thermore, these instruments allow investigators to consider excluding subjects based on the presence of motor side effects. Tardive dyskinesia, for example, is associated with cognitive and psychophysiological dysfunction, which may warrant the exclusion of patients with this symptom (for a discussion see Spohn & Strauss, 1989).

Acknowledgmen& - Preparation of this article was supported in part by National Institute of Rnental Health Grant MH44116 to John M. Neale. Jack J. Blanchard was also supported, in part, by National Institute of Mental Health Grant MH18932 for the Collaborative Training Program in

Schizophrenia Research at the Medical College of Pennsylvania at EPPI.

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Received May 10, 1991 Accepted September 12, 1991

medication effects: conceptual and methodological issues in schizophrenia research

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