DEPRESSION AND ANXIETY 4:257267 (1996/1997)

Review Article
ONSET OF ANTIDEPRESSANT ACTIVITY: REEXAMINING THE STRUCTURE OF DEPRESSION AND MULTIPLE ACTIONS OF DRUGS
Martin M. Katz,1* Stephen H. Koslow,2 and Alan Frazer3 The question of when antidepressant drugs (AD) initiate significant clinical actions in depressed patients is still unsettled. Findings from early studies on whether there is a lag in the onset of therapeutic actions were in disagreement. More recent results with the selective serotonin reuptake inhibitors (SSRIs) and other new ADs indicate that clinical actions occur within the first 2 weeks. In this paper, evidence from efficacy studies with the ADs is reviewed and the methodologic and conceptual obstacles to achieving definitive results about the onset issue are analyzed. Depression, formerly viewed as a homogenous disorder, is now seen as heterogenous and multifaceted in structure. Such major structural components as anxiety and disturbed psychomotor functioning can be as significant to the core of the disorder as depressed mood itself. Further, the ADs have been shown to act initially on different facets of the clinical disorder which then result in multiple clinical actions, e.g., an initial reduction in anxiety followed by stimulation of motor activity. Data from the NIMH Collaborative Study of the Psychobiology of Depression are used to illustrate: (1) the componential structure of severe depressive disorder; (2) the sequence of change in the major behavioral components of the disorder associated with the tricyclic drugs; (3) the consequent multiple onsets of clinical actions; and (4) measurement of the clinical significance and visibility of the early behavioral changes. Recent results describing new behavioral and methodological approaches, the use of early clinical changes to predict outcome, and strategies for designing sound studies of onset are discussed. Depression and Anxiety 4:257267, 1996/1997. 1997 Wiley-Liss, Inc. Key words: lag period; placebo response; tricyclic antidepressants; selective serotonin reuptake inhibitors; atypical antidepressants; effect size measures
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Despite more than 30 years of research since the in-

INTRODUCTION

troduction of antidepressant drugs (ADs), the neurochemical and behavioral processes that underlie the course of recovery in depressed patients remain unclear. Uncertainty about the time of onset and the nature of the initial clinical actions of ADs have served as major barriers to progress in basic and clinical studies of antidepressant activity. In a previous paper (Katz and Maas, 1994), a principal source of the problem was identified to be the failure to track changes in specific behaviors over time in the detailed manner in which investigators have monitored and described drug-induced changes in the functioning of neurotransmitter systems (Frazer and Conway, 1984;

Department of Psychiatry, Albert Einstein College of Medicine-Montefiore Medical Center, New York, New York 2 Division of Neurosciences and Behavioral Sciences, National Institute of Mental Health, Rockville, Maryland 3 Department of Pharmacology, University of Texas Health Sciences Center at San Antonio & Audie L. Murphy Memorial Veterans Hospital, San Antonio, Texas Contract grant sponsor: National Institute of Mental Health; Contract grant numbers: U01 MH26976, 26975, 26977, 26979, 26978, 131921, 44403. *Correspondence to: Martin M. Katz, Ph.D., 6305 Walhonding Road, Bethesda, MD 20816. Received for publication 12 November 1996; Revised 17 February 1997; Accepted 10 March 1997

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Blier and de Montigny, 1994). A central unresolved issue is whether clinical effects of ADs in depressed patients lag 2 to 3 weeks behind initial drug actions on central neurotransmitter systems, or if they are concurrent with early neurochemical effects. This paper is a commentary and a review of the current status of the onset of clinical effects and attempts to place this important issue in a broader conceptual and methodological context. The question of clinical onset of antidepressant drug activity is critical to future research on their mechanism(s) of action. For example, in seeking to account for therapeutic actions of ADs, belief that there is a lag in clinical response has led to a deemphasis in research on their acute pharmacologic effects. It has, in fact, resulted in studying slowly developing or chronic effects produced by these drugs on central monoamine systems (Frazer, 1994). At the same time, belief in the lag period for onset of action has led clinicians to attribute observed early behavioral changes largely to placebo factors and, presumably, to discount them as possible predictors of later treatment response. If, on the other hand, patients who show no therapeutic response to the drug during the first week of treatment are unlikely to have a positive outcome after 4 weeks of treatment, the clinician could move more rapidly to an alternative treatment approach. Thus, in terms of enhancing the clinicians capacity to treat depression in an effective and expeditious manner, the onset issue has important implications for treatment practice. This is especially true in an inpatient setting and a managed care environment. To accomplish the objectives of the paper, we review briefly the conflicting findings and explore the background of the controversy. The reported results of the National Institute of Mental Health Collaborative Study of the Psychobiology of Depression (Katz et al., 1979; Maas et al., 1980) are used to reexamine the multifaceted structure of depression and to analyze the sequence of tricyclic drug actions on the components of behavior. We also ask whether the early behavioral effects observed in drug responders in certain studies are clinically meaningful, i.e., associated with the core of the disorder of depression; further, whether from the standpoint of clinical practice, they are of sufficient size to be useful in the prediction of therapeutic outcome. Finally, strategies are outlined for developing more definitive studies on the onset issue for new classes of antidepressants.

cussed in detail factors that complicate early detection of drug effects. Perhaps chief among these is the fact that many depressed patients do respond, at least initially, to placebo. Placebo controlled efficacy studies of ADs uniformly reveal a drop in global depression severity scores in the first 2 weeks in the placebo group. The placebo response is not necessarily due to the placebo itself but may reflect nonspecific treatment factors (e.g., hospitalization) or spontaneous remission or recovery. This necessitates, then, the use of a placebo-treated control group of patients in studies of onset of action (Prien et al., 1985) or drug induced behavioral improvement occurring early. Given the placebo response, the parameter that limits early detection of drug-specific effects is its duration and magnitude (Preskorn, 1994). When defining onset, it is important to distinguish the time at which therapeutic drug actions first appear from the occurrence of substantial improvement which signifies clinical response to an antidepressant agent. Further, it would be helpful to extend the definition of early improvement to variables other than overall severity of the disorder so as to include significant drug-initiated early change in major components of the depressive disorder. Such considerations illustrate the difficulties inherent in studies of onset of action. Standardization of definition and criteria would be useful. We suggest, based on earlier analyses of the issues, e.g., Quitkin et al. (1984), Prien et al. (1985), Stassen et al. (1993), Montgomery (1995a), that onset be defined as that time point at which significant, persistent improvement in the severity of the state of depression, or in one or more of its major clinical components, is initiated. The concepts significant improvement and major clinical components will be further defined later. The currently held assumption that there is a lag in onset has, therefore, been derived primarily from secondary evidence, i.e., from studies designed to answer other questions, notably the clinical efficacy of various ADs. Such studies have demonstrated clearly that it takes a long time, weeks if not months, for the maximal benefit due to ADs to occur. This is a different issue from the question of when the drugs begin to initiate behavioral improvement. REOPENING THE QUESTION It is noteworthy that Kuhn (1958), in his landmark study, reported that the initial positive response of the majority of depressed patients to imipramine was within the first few days. This observation was later reinforced by Angst (1970) following a review of clinical efficacy studies. Kuhns observations were strongly supported in early studies conducted by Braithwaite et al. (1972), Haskell et al. (1975), Zeigler et al. (1977), and Small et al. (1981) in which tricyclic drugs were shown to produce rapid improvement of key symptoms in treatment-responsive patients. Later, however, the combined weight of the secondary evidence

BACKGROUND
DEFINING ONSET It is of special concern that a search of the literature has not uncovered any studies that provide an unequivocal answer to when the onset of AD clinical activity begins. (See Prien et al., 1985 for an earlier analysis of the methodologic requirements for such studies). Also, the definition of onset has not necessarily been standardized. Preskorn (1994) has dis-

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from controlled clinical trials of tricyclic drugs, together with a series of novel studies associating early behavioral effects with the placebo response (Quitkin et al., 1984,1987), seemed to clearly support a delay of some 2 to 3 weeks before the clinical actions of ADs became manifest. Although these latter studies were conducted only with outpatients, the notion of a lag for onset of clinical action became lore. It was incorporated into pharmacologic and psychiatric textbooks and has been generally accepted. A review of research over the last two decades has led to a reexamination of the validity of the lag notion. This research can be categorized as follows: (1) studies in which clinical changes, or the lack thereof, during the first week are shown to be predictive of treatment outcome (Zeigler et al., 1977; Coryell et al., 1982; Nagayama et al., 1991); (2) studies of the sequence of drug-associated behavioral actions which demonstrate correlations of the earlier changes with concentrations of the drug in plasma (Katz et al., 1987,1991; Casper et al., 1994); and (3) clinical trials of new types of antidepressants which, although not specifically designed to estimate the earliest time of clinical response, indicate an onset of action within 7 to 14 days of treatment e.g., selective serotonin reuptake inhibitors (SSRIs) Tollefson and Holman, 1994; Dunbar et al., 1991), moclobemide (Gachoud et al., 1992), venlafaxine (Rickels et al., 1995; Derivan et al., 1995; Montgomery, 1995b), and mirtazapine (Smith et al., 1990). These studies have found, on the one hand, the early changes to be clinically significant, whereas, on the other, they fall short of meeting all the requirements of a controlled study of onset. They provide examples of the methodologic complications in deriving definitive results on this issue. Thus, they have reopened the question and will be discussed in more detail later in the paper. Others have also recently addressed specific methodologic issues relevant to appropriately designed onset studies (Laska and Siegel, 1995; Leber, 1995; Montgomery, 1995a; Overall, 1995). METHODOLOGIC AND CONCEPTUAL OBSTACLES TO MEASURING MULTIPLE ONSETS What is the correct answer to the onset question? Prien et al. (1985) listed the methodologic requirements for a study of onset of action. They include: (1) establishment of predetermined criteria for a change to be considered clinically significant; (2) frequent clinical assessments; (3) appropriately aggressive dosage schedules; (4) adequate sample size; and (5) a placebo control. Few, if any, studies have met all of these requirements. One can add that it is necessary in studies designed to determine onset to focus on treatment responders, patients with a positive outcome after some fixed, reasonable treatment trial (e.g., at least 4 weeks but preferably longer). The standard clinical drug trial designed to study the efficacy of an AD has its major focus on the comparison of the average over-

all response of drug-treated vs. placebo treated patients; it does not usually allow for examination of a possible early onset (especially with respect to specific behaviors) in the subgroup of treatment responders. There are additional conceptual barriers to solving the problem. Overcoming them involves a shift in approach or perspective from the model used to study the efficacy of a drug for a specific mental disorder. They require taking into account information concerning: (1) the clinical phenomena of the disorder of depression; namely, that depression is not unitary, but multifaceted (Klerman, 1972), comprised of several significant emotional, cognitive, and behavioral components; and that (2) the tricyclic and the newer antidepressant drugs have multiple behavioral effects on the disorder (Kielholz and Poldinger, 1968) which derive from multiple actions on the functioning of central neurotransmitter systems (e.g., Carlsson et al., 1969). These clinical components may change at different rates during the course of treatment (Lader et al., 1987; Haskell et al., 1975; Katz et al., 1987). This implies that there is no single onset of action to determine, but rather multiple onsets, i.e., discrete time points at which the drugs initiate change in various clinical components. Thus, a study aimed at determining onset must not only assess the depressive state frequently during the course of treatment but must also include measures of the primary components of the depressive disorder.

ON THE STRUCTURE AND CORE OF DEPRESSION

Extant theories of the nature of depression differ as to which components of depression are of major significance to the disorder as a whole. Classical theory recognizes disturbances of psychomotor and somatic function as specific signs of melancholia (Parker et al., 1990); the focus of cognitive theory is on disturbances in thought content (Beck, 1972), and other viewpoints including the psychoanalytic focus on hostility or suppressed feelings of anger (Abraham, 1911; Freud, 1934). The theories differ with regard to the concept of the core component, i.e., whether the disorder is primarily affective or cognitive in origin, but are in agreement that multiple facets are required to define the state. This shift in concept is now explicitly recognized by the DSM-IV and ICD-10 guidelines for the diagnosis of major depression; they describe a syndrome that is composed of multiple signs and symptoms. In order to examine the influence of this multifaceted structure in uncovering the course of drug action, certain results of the Collaborative Study of the Psychobiology of Depression are described. This study was not aimed directly at determining onset of AD activity but included comprehensive behavioral analysis of the baseline depressive state, relatively rapid administration of amitriptyline or imipramine during the first week to achieve a high steady dosage, and early

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TABLE 1. Dimensions of the severe depressive statea

Dimension 1. Depressed mood-retardation 2. Anxiety-agitation-somatization-sleep disorder 3. Hostility-interpersonal sensitivity
a

% Variance 26 28 21

the state. Effects of the antidepressants on each of the major clinical components, as well as changes in the overall state of depression and central depressed mood, need to be measured.

Source: Katz et al. (1984). b Based on principle components analysis of 11 state construct values in a hospitalized sample of depressed patients (n = 73).

THE ONSET, SEQUENCE AND NATURE OF TRICYCLIC DRUG ACTIONS IN DEPRESSION

In the Collaborative Study (Katz et al., 1987), patients must have appeared to recover completely or nearly completely on several clinical indices to have been classified as responders, i.e., combined quantitative Global Adjustment Scale (GAS; Endicott and Spitzer, 1978), Global Improvement Scale, and Hamilton ratings indicated no further evidence of psychiatric disorder. Then, the nature and sequence of changes in the component behaviors in the responder group over the 4 weeks of treatment were identified (Katz et al., 1987,1991). As a comparison group, patients showing little or no therapeutic response to 4 weeks of treatment (the nonresponders) were used. Since the Collaborative Study did not include a placebo treatment group, a further analysis was conducted to determine which of the behavioral changes that initially distinguished the responders from the non-responders were correlated with the concentration of the drug and/or its major metabolite in plasma. This analysis would not in itself indicate that the behavioral changes were drug initiated, but significant correlations would provide strong ancillary evidence that the behavioral effects were associated with the actions of the drug (Katz et al., 1991). At the end of the first week, significant differences between responders and nonresponders included changes in anxiety, hostility, depressed mood, distressed expression and agitation. The early changes were then examined to determine which correlated positively with drug or drug metabolite concentration in the plasma. The three behavioral changes that met the two conditions for treatment with amitriptyline are displayed in Figure 1; they were: reductions in anxiety, hostility, and distressed physical expression. It should be noted, by comparison, that the early reduction in sleep disorder occurred in both the responder and nonresponder groups. This presumably reflects a sedative effect that was not found to be associated with a later positive outcome. The early effects were followed at 2 weeks by an increase in social adaptation, and marked reductions in depressed mood and motor retardation. Results with imipramine (unpublished) led to similar conclusions. The tricyclic drugs, therefore, appeared to have both tranquilizing (calming) and stimulating actions. These drugs act, then, on the two opposing affective qualities in severe depressive disorders, i.e., the depressed mood-motor retardation component and the anxiety-agitation-somatization or arousal component.

and frequent measurement of the impact of drugs on the major affective and behavioral components. Further, the behavioral and affective structure of the severe depressive disorder was analyzed in a large sample of hospitalized unipolar and bipolar patients through application of a range of clinical methods, e.g., Hamilton Depression Scale (1960), SCL-90 (Derogatis et al., 1974), video measures of expressive and affective state (Katz et al., 1982). It was determined that the variance across behavioral, cognitive, affective and psychomotor aspects of the state could be explained in large part (75% of the variance) by three dimensions: (1) anxiety-physical agitation-somatization; (2) depressed mood-motor retardation; and (3) hostility-interpersonal sensitivity (Katz et al., 1984; see Table 1). The first two were found to have equal strength in the overall structure. Other elements related to these dimensions in varying degrees included cognitive impairment, measures of physical distress, and disturbed social behavior. In accord with earlier research on the phenomenology of depression (Grinker, 1961; Paykel, 1971) it is clear that affects such as anxiety and hostility play major roles in its dynamics and expression. Because of the prominence of these affects alongside the central feature of depressed mood, this study showed that these behaviors and affects should be viewed as major components whose interaction defines the multifaceted nature of the disorder, and not be viewed as merely symptoms of the illness. The state of depression, in accord with the multifaceted view, can then be interpreted as consisting of at least two relatively opposed states (in terms of central nervous system arousal), a depressed mood-motorically retarded dimension and an anxious-physically agitated dimension, which coexist in most severely depressed patients. Although the clinical concept of anxious depression is not new (Overall, 1962; Paykel, 1971), treating the opposed states as equal in presence acknowledges that anxiety is a major component of the disorder rather than a sign or symptom of the underlying disease. Viewing the facets as components which interact to create the disorder has implications for how drug actions are interpreted. Central noradrenergic and serotonergic systems may coordinate or regulate different types of behavior; therefore, activation or inhibition of these neuronal systems by ADs could cause different specific effects in various behavioral components of

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Figure 1. Differences between responder and nonresponder groups in behavioral changes during the first 21 days of amitriptyline treatment. Source: Katz et al. (1991).

ON EARLY ACTIONS AND PREDICTING OUTCOME In accord with Kuhns (1958) original finding, the studies of Braithwaite et al. (1972), Zeigler et al. (1977), Small et al. (1981), and Haskell et al. (1975) indicated that the most dramatic improvement with the tricyclic drugs was during the first week. In addition, early (Di Mascio et al., 1979) and more recent (Smith et al., 1990; Dunbar et al., 1991; Tollefson and Holman, 1994; Rickels et al., 1995; Montgomery, 1995b) studies report significantly greater behavioral improvement due to antidepressants within the first 2 weeks of drug treatment than that caused by placebo. This has been shown for a range of drugs including tricyclic anti-depressants (TCAs), SSRIs, venlafaxine, and mirtazapine. By contrast, Quitkin et al. (1984, 1987) initially and in more recent analyses of their earlier studies (Quitkin et al., 1996a,b), reported that early response to antidepressants is no greater than that which occurs with placebo and that there is no early drug-specific behavioral improvement associated with later positive outcome. None of these studies, i.e., those showing early improvement due to active drug or those that did not, were directly aimed at the onset issue and did not incorporate into their design the criteria proposed by Prien et al. (1985). With reference to the role of early changes in predicting outcome, Hordern et al. (1963) found that patients showing a 30% decrease in severity in the first week had a significantly better long-term response

than those who did not. There were, in fact, a number of studies that reported that a positive clinical response to tricyclics within the first 2 weeks was associated with a positive therapeutic outcome (Small et al., 1981; Coryell et al., 1982; Nagayama et al., 1991). Conversely, Coryell et al. (1982) and Hordern et al. (1963) demonstrated that failure to show any improvement within the first 2 weeks of drug treatment was clearly associated with a negative outcome. These studies indicate that early improvement, i.e., within the first 2 to 4 weeks, is associated with a positive outcome following 4 to 6 weeks of drug treatment. However, in studies which included a placebo, e.g., Small et al. (1981), despite significantly less response overall in the placebo group at 2 weeks, early responders to placebo were also more likely to have a positive therapeutic outcome. It would appear, then, that early improvement on drug could be a nonspecific reaction, i.e., those patients responding early to whatever treatment, drug or placebo, will get better following the course of treatment. More recently, Stassen et al. (1993) reached similar conclusions from their meta analysis of a multicenter efficacy study of amitriptyline, oxaprotiline and placebo. Response was considered at least a 50% reduction of the HAM-D score from baseline. They found that the time course of global improvement among responders was identical in all three treatment groups. Because of this, they speculated that once the process of recovery from depression is triggered, it is identical to that of spontaneous recovery as observed, for example, with placebo. An important aspect of the Stassen et al. (1993) analysis was the use of survival-analytic methods to take into account differences in dropout rates among the different treatment conditions. In that study, 50% of placebo-treated patients dropped out within the first 8 days, resulting in less than 50% of the patients in the initial placebo sample remaining to complete the treatment period. When dropout rates were taken into account, the outcome of a comparison of the efficacy of the two antidepressant drugs significantly changed; both active drugs were found to be significantly more efficacious than placebo. Since the number of placebo dropouts were more than twice the number of that in either drug treated sample, it is difficult to treat placebo responders and drug responders as comparable samples. SSRLS AND OTHER NEW ADS More recently, the onset issue has been examined in studies of the efficacy of the SSRIs. Boyer and Feighner (1994) analyzed data from six efficacy studies. They found that if a patient did not have at least a 20% improvement on the HAM-D score at any time during the first 3 weeks of treatment, the likelihood of a 6-week response was 17.5%. If there was no improvement during the first 4 weeks, the likelihood was only 3.7%. They concluded that if there is no improvement early in treatment, the chance of a mean-

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ingful later response (i.e., by week 6) was poor. Dunbar et al. (1991) and Tollefson and Holman (1994) reported significantly greater clinical effects due to paroxetine or fluoxetine as early as 1 week, in comparison to that due to placebo. Also of direct relevance is recent research with venlafaxine, a new antidepressant that inhibits the reuptake of both norepinephrine (NE) and serotonin (5-HT) (Rickels et al., 1995). Derivan et al. (1995) reanalyzed data from two clinical trials with outpatients in which rapid escalation of dosage was used to achieve a mean daily dose of 200 mg by the end of week 1. They then compared three methods to determine onset of clinical actions. In addition to the conventional method of direct comparison of the effects of drug and placebo on overall severity at 1 and 2 weeks of treatment, they applied the pattern approach of Quitkin et al. (1984) and survival analysis (Kaplan and Meier, 1958). All three methods showed venlafaxine to produce significant clinical improvement early, effects that were sustained throughout treatment. PATTERNS OF RECOVERY FROM DEPRESSION A few studies have attempted to examine the pattern of recovery from depression. Haskell et al. (1975) examined this in depressed outpatients treated for 4 to 6 weeks with amitriptyline. Symptoms that improved rapidly, i.e., within the first week, and in a linear fashion, were suicidal feelings, insomnia, irritability and agitation. More gradual improvement, i.e., 2 weeks or more, was noted in impaired work and interests, retardation and pessimism, and hopelessness. The patients were not separated categorically into responders and nonresponders, so it is unclear what early behavioral changes occurred exclusively in drug-responsive patients. As mentioned previously, Katz et al. (1987) reported a similar progression of changes in inpatients who responded to treatment, i.e., anxiety and hostility were reduced the first week, and change in motor retardation occurred later (between 2 and 3 weeks). Small et al. (1981) evaluated the efficacy of trazodone, imipramine or placebo. Patients were classified categorically as responders or nonresponders after 4 weeks of treatment. Data were presented for five individual factors from the HAM-D scale. The two active drugs were nearly indistinguishable in showing improvement on the five factors but they were uniformly better than placebo. However, the profiles of response were similar for both active treatments and the placebo group. They concluded that recovery from depression by any therapeutic intervention (including placebo) is consistent in terms of the kinds of improvement observed during the first 4 weeks of treatment. This conclusion is open to question; the HAM-D factors have limited sensitivity in differentiating types of improvement. Other studies have demonstrated that different treatments for depression have different effects, e.g., the DiMascio et al. (1979) study of the early effects of the tricyclics and of psychotherapy, and

that when studying drug effects on the facets of affect and physical distress, they appear highly differentiated (see Haskell et al., 1975; Lader et al., 1987). MEASURES OF EARLY RESPONSE A common method for estimating onset is to determine the first time point at which a significant difference on a general measure of efficacy is found between the effects of active drug and placebo. Quitkin et al. (1984) pooled week 1 and week 2 data from three clinical trials of various antidepressants, to contrast drug and placebo effects on the Clinical Global Impression Scale (CGI). To detect improvement at week 1, they used the same criterion that they used to measure clinical outcome at 6 weeks, i.e., a CGI rating of 1 (very much improved) or 2 (much improved). A rating of 2 signifies a minimum of 75% reduction in the intensity and frequency of depressed mood (Quitkin et al., 1996a). Utilization of such a high level of improvement to identify onset may not be justifiable since the most commonly used index for a positive therapeutic outcome after an entire course of treatment is a 50% change in the initial HAM-D total score. Montgomery (1995a) discussed this issue and reviewed several approaches to measuring clinically relevant early response in onset studies. Based on the recent results from the Dunbar et al. (1991) and Tollefson and Holman (1994) studies, he distinguished the concepts of early improvement and recovery. The concepts differ by degree, and could be measured along a common scale of severity, the HAM-D or the MADRS, or on a scale of global improvement. When this approach was combined with the Stassen et al. (1993) survival analysis, Montgomery (1995a) reported that patients showing a sustained early improvement of 20% at 10 days went on to reach the conventional 50% reduction criterion to be a responder at 4 weeks. Montgomery (1995a) and Stassen et al. (1993) should be commended for emphasizing the temporal distinction between early improvement and recovery. When working with the multifaceted concept of depression, measurement of early improvement requires further extension in order to identify changes in major components or specific facets of the clinical state. A method is described below which applies the quantitative index of effect size to extend this approach from analysis of overall severity to measuring changes in the components of the depressed state.

ON MAGNITUDE OF EARLY CHANGE IN MAJOR COMPONENTS OF DEPRESSION AND THEIR CLINICAL SIGNIFICANCE
Are the initial statistically significant changes in behavioral components of depression of sufficient

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Figure 2. Comparison of rating vantages and overall measure of severity of depressed state at 1 week of treatment with tricyclic drugs: effect sizes of differences between responders and all other patients.

Figure 3. Comparison of rating vantages and overall measure of anxiety at 1 week of treatment with tricyclic drugs: effect sizes of differences between responders and all other patients.

magnitude to be usefully applied clinically? That is, if they are predictive of later response to treatment, are the early changes in the responder of sufficient size, i.e., greater than those in all other treated patients, to be observable by the clinician? To address the question of magnitude of change of a specific facet of the disorder in the Collaborative Study (Katz et al., 1987), the statistical index, effect size, derived by Cohen (1969), was used to measure the difference between change in the responders and change in all other drug-treated patients, at the 1- and 2 1/2-week time points. The effect size index assesses the physical size of a statistically significant group difference. The technical procedure involves measuring the mean difference between groups in terms of standard deviation units. An effect size score of 0.2 would be viewed as physically small by Cohen (1969); 0.5 as medium and 0.8 as large. A medium score is considered large enough to be visible. The implication is that the larger the effect size the more likely that the differences (in this case between observational ratings) are visible or detectable in clinical practice. Figure 2 provides an example of how results using effect size changes would be interpreted. It shows why there can be ambiguity at the end of the first week about whether the statistically significant change in behaviors in eventual responders is sufficiently larger than that in the patients who did not respond, to be observable. The construct measure of the overall state of depression combines the vantages of the doctor, the nurse and the patients self-report to provide an overall score. The overall score indicates a difference in the amount of change in the responder and all other patients as visible (0.58) but not particularly robust. The effect size based on the nurses ratings alone is comparable to the overall score. However, when the doctors ratings alone are examined, it is clear that the

difference is very large and robust (0.97) and, accordingly, quite visible. The doctors see a major difference between the improvement in responders and all other patients on this overall state measure after just 1 week. By contrast, the effect size for the patients self ratings is small (0.24), indicating that the patients who ultimately responded reported very little improvement, if any, at this time in their overall state of depression. When the specific construct of depressed mood (part of the overall depressed state) was examined, this conclusion was reinforced; the findings were found to be highly similar in pattern to those with depressed state (data not shown). By contrast, the results for anxiety (one of the constructs determined earlier to clearly change in responders at 1 week) agree among the various raters at 1 week. The overall construct measure shows a large change, one that is visible in responders (compared with all other treated patients) in the eyes either of the doctor, the nurse, or the patient (Fig. 3). It can be concluded, then, that the early (one week) change in anxiety, found to be significantly larger in responders than in all other patients, and found to be associated with the concentration of drug in the plasma, was sufficiently large to be observable by clinicians in practice. Use of this construct difference (and those found with hostility and distressed expression) at 1 week made it possible to classify 79% of the eventual responders and nonresponders correctly at this time (Katz et al., 1987). Thus, these changes are potentially useful as predictors of the patients response to the course of treatment and would allow the clinician to judge early in the course of treatment (based, for example, on the amount of change in anxiety and hostility) whether the patient is likely to have a positive outcome. Of course, it is not possible to conclude unequivo-

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cally that the early, visible improvement is specifically due to drug, since the Collaborative Study, did not include a placebo treatment arm. We are carrying out a new study with patients comparable to those in the Collaborative Study) that does contain a placebo treatment group. The results of this study should permit definitive conclusions to be made about the specificity of early drug effects in moderately to severely depressed patients. Our conclusions and those of others cited above stand in stark contrast to those of Quitken et al. (1984, 1987, 1991a,b, 1993). They used a novel approach, pattern analysis (Rothchild and Quitkin 1992), to try to differentiate true drug from placebo responses. According to their results, the early reduction of depression rating scores seen with active drugs is not a true drug effect but rather is a placebo effect. True drug effects are characterized by a 2-week delay in onset followed by persistent improvement; further, gradual improvement on placebo may be due to spontaneous remission. More recently, Quitkin et al. (1996a,b) pooled data from several of their earlier clinical drug trials (patients treated with either imipramine, amitriptyline, desipramine, mianserin, or three different MAOIs including deprenyl) so as to reexamine the issue of onset of response. In one analysis, they found that 32% of the patients who received drug and 10% of the patients who received placebo and who never improved even minimally within the first 3 weeks were rated as responders at week 6. Similar trends were seen with those who were minimally improved after either 4 or 5 weeks of treatment. Such data were considered to be supportive of the idea for a lag in the onset of the effect of antidepressants. Following the type of analysis used in the Collaborative Study, Quitken et al. (1996b) used the effect size measure on the same data to determine whether responders and nonresponders can be distinguished on the basis of their early response at 1 and 2 weeks of treatment. They reported that the proportion of drugtreated patient responders who showed much improvement in the first week did not differ significantly from the proportion of placebo-treated responders who were much improved in the first week. Because of this, they concluded that when the effects of nonspecific improvement are partialled out, there is no evidence of drug-specific effects early in treatment. Particularly striking in the Quitkin et al. (1996b) analysis is the small effect sizes for the contrasts between responders and nonresponders within the drug and placebo groups, 0.24 and 0.31, respectively. The effect size of the difference between groups in the Collaborative Study, for the clinicians judgment measure of the severity of the depressed state, was 0.90. These figures contrast sharply with the figures for the drug group in the study by Quitkin et al. (1996b). There are several reasons for this apparently large difference in the impact of treatment in the two studies. The studies of Quitkin and associates used outpatients

only, described as mild to moderately depressed in which 24% of patients showed a significant clinical response to placebo, i.e., a CGI score of 2 or 1 signifying a reduction of 75% in the intensity of depressed mood, during the first 2 weeks of placebo treatment. More than half of the patients studied by Quitkin and associates met criteria for being atypically depressed, but only about 30% met research diagnostic criteria (RDC) for being endogenous. Among the various drugs used, the study dosages for imipramine and amitriptyline were 200 mg/day and 150 mg/day, respectively. These dosages were, however, not achieved until after 15 days of treatment for the large majority of the patients. It is likely, therefore, that the treatment dosages during the first week were rather light. The Collaborative study sample was of inpatients, hospitalized for severe depression (mean HAM-D score of 28). Atypical depressed patients were excluded from the study and about 7585% were endogenous (Stokes et al., 1984). During a pretreatment phase in which all patients received placebo for a period of 2 weeks, only 4% had to be dropped from the treatment study because of a positive clinical response. The study dosage was 250 mg/day of amitriptyline or imipramine and was administered rapidly so that this study dose was achieved for 87% of the patients by the end of the first week. These factors, i.e., the nature of the study population, the amount and rate of drug administered during the first 2 weeks of drug treatment, and the criteria used to determine onset, are obviously critical for determining the time of onset of action of antidepressant drugs. Given these differences between the studies, it is perhaps not surprising that different results were obtained and different conclusions drawn.

SUMMARY AND CONCLUSIONS

The assumption of a lag in the clinical actions of antidepressants stems from controlled studies in which the active drug did not elicit greater improvement than placebo did in the depressed state until the third or fourth week of treatment. Conclusions from such studies are open to question because in most of them the outpatient samples represented the milder forms of the disorder, i.e., were not assay-sensitive (Montgomery, 1995a), optimal study dosage was not achieved until at least 2 weeks of treatment, and measures sensitive to change in various critical facets of the disorder, such as anxiety and psychomotor disturbance, were not included. Although evidence that the actions of antidepressants begin within the first week is also not conclusive, there are data indicating early drug-associated behavioral improvement to be predictive of a positive therapeutic outcome. Further, it seems clear that no or minimal improvement within the first 2 weeks is associated with a negative therapeutic outcome. These results, as might be expected, are more compelling in studies of the severely ill, hospitalized patients where placebo reactivity appears to play a

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lesser role. More recent studies with the SSRls, venlafaxine and mirtazapine, which include placebo controls and new statistical approaches for estimating onset, reinforce these overall conclusions. To resolve the issue of onset, it is necessary to reexamine the problem in the light of current theory about the nature of depression and new evidence about the multiple actions of the drugs on disturbed behavior. ON THE STRUCTURE OF DEPRESSION Disturbances in affect, cognition, behavior and somatic functioning are major and equally significant components of the disorder. Thus, depression is now viewed as a multifaceted disorder. Recent findings indicate the strong presence of opposed states of arousal in severe depression. A dimension of agitation, anxiety and somatic disorder coexists with a dimension of depressed mood and motor retardation. They occur in addition to elements of greater than normal hostility and cognitive impairment. THE SEQUENCE AND NATURE OF ANTIDEPRESSANT DRUG ACTIONS Studies of the tricyclic drugs indicated that the drugs had multiple clinical actions on the state of depression. These included sequential reductions of the disturbed affects of anxiety, hostility, depressed mood, and of motor retardation. The sequence of effects was interpreted as an initial calming of the organism, followed closely by a stimulatory action. It is likely that since a number of the newer drugs, e.g., the SSRIs, impact central neurotransmitter systems differently than the tricyclics, that the initial effects, and the sequence and types of behavioral change they produce, will differ from those caused by the TCAs. Because of limitations in the behavioral methods applied to the problem, this prediction is yet to be tested adequately. THE MEANING AND MAGNITUDE OF EARLY ONSET Both current theory and evidence support changes in the level of anxiety and hostility to be as meaningful to the disorder of depression as are the changes in depressed mood. The question remains as to whether the initial drug-associated changes in these major components are of sufficient size to be useful in prediction of outcome, and to be visible early to the clinician. Evidence is presented demonstrating that at the end of the first week of treatment with tricyclic drugs, improvement in depressed mood is ambiguous. Early first week reductions in anxiety and hostility, however, are both associated with response to 4 weeks of treatment and are sufficiently large to be reported by patients. In the case of anxiety, the change is easily detectable by doctors and nurses. Clinicians can, therefore, use these early changes, or the lack thereof, to predict whether a patient is likely to be responsive or not and to adjust his/her treatment accordingly. Recent findings with the SSRIs and venlafaxine also

indicate significant clinical actions within the first week or 10 days. IMPLICATIONS FOR BASIC STUDIES OF THE MECHANISMS OF ANTIDEPRESSANT ACTION The evidence is strong, therefore, that antidepressants begin to act early on the disorder of depression, but not necessarily on the elements of depressed mood and motor retardation. They clearly act early on components that most clinical theorists would now accept as major elements of the disorder. Thus, where the objective is to identify early predictors of outcome, it is necessary to first determine the onsets of multiple clinical actions. In order to understand the underlying mechanisms of drug efficacy, i.e., the nature of the interaction of neurochemical and behavioral factors in bringing about recovery, the course of change of the various behaviors must be tracked in treatment responders (alongside the changes in functioning of neurotransmitter systems). METHODOLOGIC REQUIREMENTS TO ACHIEVE DEFINITIVE RESULTS In order to distinguish between early nonspecific effects of treatment and the effects of the active drug, a placebo control group is essential. Appropriately aggressive dosage schedules are required (Prien et al., 1985) as well as a study sample that is assay-sensitive, i.e., comprised of those depressed patients where a low placebo response rate is expected (Montgomery, 1995a). The detection of early onset can be further enhanced by developing separate criteria for early improvement and for full response or recovery. Because of the high dropout rate for placebotreated patients, it is useful to apply survival analysis. Studies will require methods for clear separation of treatment responders and norresponders and for measuring change in the multiple behavioral components of depression. Studies that fully integrate this kind of conceptual and methodological information have yet to be carried out.

REFERENCES
Abraham K (1911) Notes on the psychoanalytical investigation and treatment of manic-depressive insanity and allied conditions. In Jones E (ed): Selected Papers on Psychoanalysis. London: Hogarth Press, pp 137-156. Angst J (1970) Mechanisms of action of imipramine and its therapeutic use. In: Angst J (ed): Tofranil Stampflu and Cie Bern, p 36. Beck AT (1972) Depression: Causes and Treatment. Philadelphia: University of Pennsylvania Press. Blier P, de Montigny C (1994) Current advances and trends in the treatment of depression. Trends Pharmacol Sci 15:220-226. Boyer CL, Feighner JP (1994) Clinical significance of early nonresponse in depressed patients. Depression 2:32-35. Braithwaite R, Goulding R, Theano G, Bailey J, Coppen A (1972) Plasma concentration of amitriptyline and clinical response. Lancet 1:12971300.

266

Katz et al.

Carlsson A, Corrodi H, Fuxe K, Hokfelt T (1969) Effect of antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl--ethyl-meta-tyramine. Eur J Pharmacol 5:357366. Casper RC, Katz MM, Bowden CL, Davis JM, Koslow SH, Hanin I (1994) The pattern of physical symptom changes in major depressive disorder following treatment with amitriptyline or imipramine. J Affect Disord 31:151164. Cohen J (1969) Statistical Power Analysis for the Behavioral Sciences. New York, NY: Academic Press. Coryell W, Coppen A, Zeigler VE, Biggs JT (1982) Early improvement as a predictor of response to amitriptyline and nortriptyline: A comparison of two patient samples. Psychol Med 12:135139. Derivan A, Entsuah AR, Kikta D (1995) Venlafaxine: Measuring the onset of antidepressant action. Psychopharmacol Bull 34:437-445. Derogatis LR, Lipman RS, Rickels K, Uhlenhuth EH, Covi L (1974) The Hopkins Symptom Checklist (HSCL): A measure of primary symptom dimensions. In Pichot P(ed): Psychological Measurements in Psychopharmacology: Modern problems in Pharmacopsychiatry Vol 7. Basel: Karger, pp 79110. DiMascio A, Weissman, MM, Prusoff BA, Neu C, Zwilling M, Klerman GL (1979) Differential symptom reduction by drugs and psychotherapy in acute depression. Arch Gen Psychiatry 36:1450-1456. Dunbar GC, Cohn JB, Fabre LF, Feighner JP, Fievre RR, Mendels J, Shrivastava RK (1991) A comparison of paroxetine, imipramine and placebo in depressed outpatients. Br J Psychiatry 159:394-398. Endicott J, Spitzer R (1978) A diagnostic interview: the Schedule of Affective Disorders and Schizophrenia. Arch Gen Psychiatry 35:837844. Frazer A (1994) Antidepressant drugs. Depression 2:119. Frazer A, Conway P (1984) Pharmacologic mechanisms of action of antidepressants. Psychiat. Clin North Am 7:575-586. Freud S (1934) Mourning and melancholia. In: Collected Papers, Vol. 4 London. Hogarth Press, pp 153-170. Gachoud JP, Mikkelsen H, Ammar S, Widlocher D, Jouvent R (1992) Theoretical considerations and perspectives on the onset of action of moclobemide. Psychopharmacology 106:S96-S97. Grinker RR Sr, Miller J, Sabshin M, Nunn R, Nunnally JC (1961) The Phenomena of Depressions. New York: Hoeber. Hamilton M (1960) A rating scale for depression. J Neurol, Neurosurgery, and Psychiatry 23:5662. Haskell DS, DiMascio A, Prusoff B (1975) Rapidity of symptom reduction in depressions treated with amitriptyline. J Nerv Ment Dis 160:24-33. Hordern A, Holt NF, Burt CG, Gordon WF (1963) Amitriptyline in depressive states. Brit J Psychiatry 109:815825. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481. Katz MM, Koslow SH, Berman N, Secunda S, Maas JW, Casper R, Kocsis J, Stokes P (1984) Multivantaged approach to the measurement of behavioral and affect states for clinical and psychobiological research. Psychol Rep. 55:619791. Katz MM, Koslow SH, Maas JW, Frazer A, Bowden CL, Casper R, Croughan J, Kocsis J, Redmond E (1987) The timing, specificity, and clinical prediction of tricyclic drug effects in depression. Psychol Med 17:297309. Katz MM, Koslow SH, Maas JW, Frazer A, Kocsis J, Secunda S, Bowden CL, Casper RC (1991) Identifying the specific clinical actions of amitriptyline: Interrelationships of behavior, affect and plasma levels in depression. Psychol Med 21:599611. Katz MM, Maas JW (1994) Psychopharmacology and the etiology

of psychopathological states; Are we looking in the right way? Neuropsychopharmacology 10:139-144. Katz MM, Robins E, Croughan J, Secunda S, Swann A (1982) Behavioral measurement and drug response characteristics of unipolar and bipolar depression. Psychol Med 12:2536. Katz MM, Secunda S, Hirschfeld RM, Koslow SH (1979) NIMH Clinical Research Branch Collaborative Program on the Psychobiology of Depression. Arch Gen Psychiatry 43:765771. Kielholz P, Poldinger W (1968) Die behandlung endogener depressionen mit psychopharmaka. Dt med Wschr 93:701704. Klerman GL (1972) Clinical phenomenology of depression: Implications for research strategy in the psychobiology of the affective disorders. In: Williams TA, Katz MM, Shield JA (eds): Recent Advances in the Psychobiology of the Depressive Illnesses. Washington DC:US Govt. Printing Office, pp 331339. Kuhn R (1958) The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J Psychiatry 115:459464. Lader M, Lang RA, Wilson GD (1987) Patterns of improvement of depressed inpatients. Maudsley Monograph No. 30; Oxford University Press. Laska EM, Siegel C (1995) Characterizing onset in psychopharmacological clinical trials. Psychopharmacol Bull 31:2935. Leber P (1995) Speed of onset. Psychopharmacol Bull 31:37. Maas JW, Koslow SH, Davis J, Katz MM, Mendels J, Robins E, Stokes P, Bowden CL (1980) Biological component of the NIMH Clinical Research Branch Collaborative Program on the Psychobiology of Depression I; Background and theoretical considerations. Psychol Med 10:759776. Montgomery SA (1995a) Are 2-week trials sufficient to indicate efficacy? Psychopharmacol Bull 31:4144. Montgomery SA (1995b) Rapid onset of action of venlafaxine. Int Clin Psychopharmacol 10: Suppl 2:2127. Nagayama H, Nagano H, Ikezaki A, Tashiro T (1991) Prediction of efficacy by 1-week test therapy in depression. J Affect Disord 23:213216. Overall JE (1962) Dimensions of manifest depression. Psychiatric Res 1:239245. Overall JE (1995) Justifying a fast acting claim for antidepressant drugs. Psychopharmacol Bull 31:4555. Parker G, Hadzi-Pavlovic D, Boyce P, Wilhelm K, Brodzky H, Mitchell P, Hickie I, Eyers K (1990) Classifying depression by mental state signs. Brit J Psychiatry 157:5565. Paykel ES (1971) Classification of depressed patients: A cluster analysis derived grouping. Br J Psychiatry 118:275-288. Preskorn SH (1994) Antidepressant drug selection: Criteria and options. J Clin Psychiatry 55:6-22. Prien RF, Blaine JD, Levin J, (1985) Antidepressant drug therapy; The role of the new antidepressants. Hosp Community Psychiatry 36:513516. Quitkin FM, McGrath PJ, Rabkin JG, Stewart JW, Harrison W, Ross DC, Tricamo E, Fleiss J, Markowitz J, Klein DF (1991b) Different types of placebo response in patients receiving antidepressants. Am J Psychiatry 148:197204. Quitkin FM, McGrath PJ, Stewart JW, Ocepek-Welikson K, Taylor BP, Nunes E, Deliyannides D, Agosti V, Donovan SJ, Petkova E, Klein DF (1996a) Chronological milestones to guide drug change. Arch Gen Psychiatry 53:785792. Quitkin FM, McGrath PJ, Stewart JW, Taylor BP, Klein DF, (1996b) Can the effects of antidepressants be observed in the first two weeks? Neuropsychopharmacology 15:390394. Quitkin FM, Rabkin JG, Markowitz JM, Stewart JW, McGrath PJ, Harrison W (1987) Use of pattern analysis to identify true drug response; A replication. Arch Gen Psychiatry 44: 259264. Quitkin FM, Rabkin JG, Ross D, Stewart JW (1984) Identification

Review Article: Onset of Antidepressant Activity

267

of true drug response to antidepressants. Arch Gen Psychiatry 41:782786. Quitkin FM, Rabkin JG, Stewart JW, McGrath PJ, Harrison W, Ross D, Tricamo E, Fleiss J, Markowitz J, Klein DF (1991a) Heterogeneity of clinical response during placebo treatment. Am J Psychiatry 148:193196. Quitkin FM, Stewart JW, McGrath PJ, Nunes E, Ocepek-Welikson K, Tricamo E, Rabkin JG, Kein DF (1993) Further evidence that a placebo response to antidepressants can be identified. Am J Psychiatry 150:566570. Rickels J, Derivan A, Entsuah R, Miska S, Rudolph R (1995) Rapid onset of antidepressant activity with venlafaxine treatment. Depression 3:146153. Rothchild R, Quitkin FM (1992) Review of the use of pattern analysis to differentiate true drug and placebo responses. Psychother Psychosom 58:170177. Small JG, Milstein V, Kellams JJ, Small IF (1981) Comparative onset of improvement in depressive symptomatology with drug

treatment electroconvulsive therapy, and placebo. J Clin Psychopharmacol 1(Suppl. 6):6269S. Smith WT, Glaudin V, Panagides J, Gilvary E (1990) Mirtazapine vs amitriptyline vs placebo in the treatment of major depressive disorder. Psychopharmacol Bull 26:191196. Stassen HH, Delini-Stula A, Angst J (1993) Time course of improvement under antidepressant treatment: A survival-analytical approach. Eur Neuropsychopharmacol 3:127-135. Stokes PE, Stoll PM, Koslow SH, Maas, JW, Davis JM, Swann AC, Robins E (1984) Pretreatment DST and hypothalamic-pituitaryadrenocortical function in depressed patients and comparison groups. Arch Gen Psychiatry 41:257267. Tollefson TG, Holman SL (1994) How long to onset of antidepressant action: A meta-analysis of patients treated with fluoxetine or placebo. Int Clin Psychopharmacol 9:245250. Ziegler V, Clayton P, Biggs J (1977) A comparison study of amitriptyline and nortryptiline with plasma levels. Arch Gen Psychiatry 34:607612.

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