Received: 28 September 2021 Accepted: 4 November 2021

DOI: 10.1002/cpp.2687

RESEARCH ARTICLE

Identifying causal mechanisms in psychotherapy: What can we

learn from causal mediation analysis?

Hugo Hesser1,2

1
School of Law, Psychology and Social Work,
Center for Health and Medical Psychology,
Örebro University, Örebro, Sweden
2
Department of Behavioural Sciences and
Learning, Linköping University, Linköping,
Sweden
Correspondence
Hugo Hesser, School of Law, Psychology and
Social Work, Örebro University, SE-701
82 Örebro, Sweden.
Email: hugo.hesser@oru.se
Abstract
Despite widespread interest in the development of process-based psychotherapies,
little is still known about the underlying processes that underpin our most effective
therapies. Statistical mediation analysis is a commonly used analytical method to
evaluate how, or by which processes, a therapy causes change in an outcome. Causal
mediation analysis (CMA) represents a new advancement in mediation analysis that
employs causally defined direct and indirect effects based on potential outcomes.
These novel ideas and analytical techniques have been characterized as revolutionary
in epidemiology and biostatistics, although they are not (yet) widely known among
researchers in clinical psychology. In this paper, I outline the fundamental concepts
underlying CMA, clarify the differences between the CMA approach and the tradi-
tional approach to mediation, and identify two important data analytical aspects that
have been emphasized as a result of these recent advancements. To illustrate the key
ideas, assumptions, and mathematical definitions intuitively, an applied clinical exam-
ple from a previously published randomized controlled trial is used. CMA's main con-
tributions are discussed, as well as some of the key challenges. Finally, it is argued
that the most significant contribution of CMA is the formalization of mediation in a
unified causal framework with clear assumptions.

KEYWORDS
causal analysis, mediation analysis, methods, potential outcomes, psychotherapy

1 | I N T RO DU CT I O N which these therapies achieve their effects (Cuijpers et al., 2019;

Fundamental to any good clinical evaluation is to ask and evaluate
theory-driven questions such as “By which mechanisms, or processes
of change, does the treatment work?” “What specific components
are responsible for activating such processes” and “Under which cir-
cumstances, or for whom, are these processes activated to such an
extent that they produce change in the outcome.” While a number
of different psychotherapy approaches are known to produce posi-
tive and clinically meaningful effects for a wide variety of clinical
conditions, little is still known about the underlying processes by
Kazdin, 2007).
In a clinical experimental setting (e.g., randomized clinical trial
[RCT]), statistical mediation analysis aims to uncover the causal path-
ways by which an independent variable (treatment vs. control) influ-
ences a dependent variable through one (or more) mediator variable(s)
(MacKinnon, 2008). In combination with a solid research design and
substantive theory, mediation analysis can be an important analytic
method to test (causal) theories on how a treatment produces change
in an outcome (Judd & Kenny, 1981). The motives for conducting
mediation within treatment evaluations are multiple as it can provide

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2 HESSER
important clues to how we can refine our treatments to be able to
pinpoint the active ingredients in better way or understand why a
treatment failed to produce a change in the outcome (Judd &
Kenny, 1981; MacKinnon, 2008; VanderWeele, 2015). Over time,
information gained from mediation analysis can be used to enhance,
modify, or develop new treatment procedures or to eliminate compo-
nents that are unnecessary (or even counterproductive).
Mediation analysis has a long history dating back to (at least) the
1950s (see Kenny, 2008; MacKinnon, 2008) and the number of arti-
cles on mediation analysis that have been published in clinical psy-
chology journals over the years demonstrates the enormous interest
in providing an in-depth theoretical understanding of how our treat-
ments work. Recent papers published in Clinical Psychology & Psycho-
therapy, for example, have employed mediation analysis to answer a
number of theory-driven and clinically relevant causal questions: Does
cognitive behaviour therapy for social anxiety disorder work by alter-
ing cognitive distortions (O'Toole et al., 2015)? Is the effect of
internet-delivered cognitive behaviour therapy on obsessive compul-
sive symptoms achieved by altering believes about obsessions
(Andersson et al., 2015)? Does an add-on dialectical behaviour
therapy-skills training for individuals with borderline personality disor-
der work by modifying assertive anger (Kramer et al., 2016)? Is the
effect of internet-delivered emotion-regulation and conflict manage-
ment training on emotional partner abuse achieved through a change
in emotion-regulation skills (Hesser et al., 2017)?
Given the recent promotion of processes-based therapies within
psychotherapy (Hofmann & Hayes, 2019), the interest in mediation
analysis is unlikely to wane in the coming years. However, mediation,
as a model describing a causal pathway by which the treatment casu-
ally influences the mediator, which, in turn, influences the outcome,
presents a number of challenges that have proven difficult to over-
come, both analytically and conceptually. In fact, several fundamental
concerns have been raised that are often overlooked by researchers
conducting mediation analysis (Bullock et al., 2010; Kline, 2015;
Spencer et al., 2005; Tate, 2015).
At the same time, methods for improving estimation and infer-
ences for mediation continue to develop (e.g., Kraemer et al., 2008;
MacKinnon, 2008; Preacher, 2015; Shrout & Bolger, 2002). These
advancements in mediation analysis also include seminal methodologi-
cal work in the field of causal modelling using the potential outcomes
framework (e.g., Imai et al., 2010; Jo, 2008; Pearl, 2014; Valeri &
VanderWeele, 2013). Several new analytical methods, known collo-
quially as causal mediation analysis (CMA) (Imai et al., 2010; Muthén &
Asparouhov, 2015), have been developed using this framework. In
fact, the major ideas emanating from this work have even been
described as revolutionary by some scholars because they offer new
analytical tools that allow for the estimation of causal quantities,
which are of critical importance for science (Glymour & Hamad, 2018;
Hernán, 2018; Pearl & Mackenzie, 2018). Yet these advancements
have been slow to reach intervention researchers in psychology,
including researchers doing clinical treatment evaluations. Part of the
reason is that many clinical psychology researchers are unfamiliar with
the statistical causal framework within which these methods were
Key Practitioner Message
• Understanding why and how psychotherapy works is criti-
cal for treatment and theory development.
• Mediation analysis is a data analytical technique used to
address why-questions in clinical trials by identifying
mediators; nevertheless, it is fraught with methodological
challenges.
• Recent advances in mediation analysis provide clinical
psychology researchers with methods to rigorously evalu-
ate mediation under clear (but strong) assumptions.
developed. In addition, since these methods have mainly been pro-
moted in technical papers published in statistical journals, many
applied researchers may find the CMA literature difficult to penetrate.
In this paper, I provide a brief introduction to CMA based on the
potential outcomes framework and offer thoughts on how these new
ideas can inform the statistical practices of mediation analysis in RCTs.
I will not go into technical details, nor is the article intended to be
comprehensive given the topic's complexity, but interested readers
are referred to sources cited throughout for a more in-depth treat-
ment of CMA. To help illustrate the key ideas intuitively, throughout
the paper, I will use an applied example from an RCT in which individ-
uals with irritable bowel syndrome (IBS) were randomized to an
exposure-based cognitive behavioural therapy or to a control condi-
tion (the same treatment without the exposure element) (see for more

tsson et al., 2014).
details about the study, Hesser et al., 2018; Ljo
Given prior theoretical and empirical evidence, it was postulated that
IBS-specific avoidance would serve as a key mediator of the effect of
exposure on IBS-symptoms (primary outcome). Thus, the purpose of
the mediation analysis is to evaluate the causal effect of the exposure
treatment on change in IBS-symptoms through its effect on change in
IBS-specific avoidance. Throughout, I will refer to the binary treat-
ment variable, T, the continuous avoidance mediator variable, M, and
the continuous IBS-symptom outcome variable, Y.
2 | THE POTENTIAL OUTCOMES
FR A M E WO RK F O R C A U SA L I N F E R EN C E
Within biostatistics, causal inferences are often couched within the
potential outcomes framework (aka. the counterfactual framework or
Rubin's causal model) where the assumptions underlying analysis
can be made explicit for the identification of causal quantities
(Rubin, 1974, 2005). In this framework, we need to consider not only
the actual realized outcome under one treatment condition but also
all the unrealized potential outcomes (counterfactual outcomes) under
all conditions. Using the potential outcomes framework, the effect of
exposure-based treatment T = 1 (vs. the control condition T = 0) on
the post-treatment outcome Y for a specific individual i can be
expressed as the difference between the outcomes, Y i ð1Þ  Y i ð0Þ,
HESSER
where Y i ð1Þ and Y i ð0Þ denote the outcome the individual would take
if exposed to treatment and control, respectively. Thus, the unit-level
causal effect of the exposure-based treatment can be expressed as
the difference in the IBS symptoms between exposure, Y i ð1Þ, and
control, Y i ð0Þ.
The problem, which was referred to by Holland as the “funda-
mental problem of causal inference” (Holland, 1986, p. 947), is that
for any individual, only one of the two potential outcomes can be
observed, and thus, even randomized experiments cannot identify the
unit-level causal effect. For a participant allocated to exposure treat-
ment, for example, we obtain the observed value of the outcome
under treatment, Y i ð1Þ, whereas the outcome that would have been
realized under control is unobserved, Y i ð0Þ. Thus, from this perspec-
tive, causal inference can be viewed as a missing data problem where
we need to make assumptions to be able to estimate unobserved out-
comes in a reasonably way (Rubin, 1974). This also means that even
though the causal effect is defined at the individual level, the effect
can only be identified and estimated using multiple individuals. We
can, however, identify and estimate the average causal effect (ACE),
which we can define, using expectations, as ACE ¼ E½Y i ð1Þ  Y i ð0Þ:
In addition to making sure that there is no interference among
individuals in a treatment trial, randomization of individuals to condi-
tions is the key to provide an unbiased ACE, as this ensures, in expec-
tation, that treatment and control conditions are balanced on
pretreatment covariates that may serve as confounders. That is, when
treatment can be randomly assigned, the observed quantities can be
used for those unobserved, opining up for making causal inference at
the average, solely based on observed data. In other words, the way
in which individuals get assigned treatment is critical and randomiza-
tion is one method that provides valid estimates of the unobserved
potential outcomes needed to obtain an unbiased ACE. More formally,
this means that T is statistically independent of potential outcomes
(aka. ignorability of treatment assignment assumption). These ideas
will be important when we extend our model to an intermediate vari-
able, that is, a mediator. When working with a continuous outcome,
the ACE can simply be identified by the posttreatment observed mean
difference between treatment and control. As individuals were
randomized to conditions in the IBS-trial, the ACE would be reflected
in the posttreatment mean difference of IBS-symptoms between
conditions.
3 | CAUSALLY DEFINED DIRECT AND
I N D I R E C T ( M E D I A T E D ) E F F E C T S BA S E D O N
P O T E N T I A L OU T C O M ES
Mediation, as an analysis that aim to uncover the variable(s) that
explains the total effect transmitted from the treatment variable to
the dependent variable, decomposes the ACE into two parts: direct
effect and indirect effect. An indirect effect can be thought of as the
part of the treatment effect on the outcome due to a change in the
mediator, whereas the direct effect is the “residual” effect that is not
transmitted via the mediator but works through other potential
3
mechanisms. Consider Figure 1 that depicts a path model from a RCT
with a single mediator, where T represents the binary treatment vari-
able (1 = treatment, 0 = control), M the continuous mediator, and
Y the continuous outcome. The most common analytical approach to
statistical mediation analysis in psychology (henceforth referred to as
the traditional approach) quantifies the indirect effect using the prod-
uct of two regression coefficients (Hayes, 2017; MacKinnon, 2008;
Preacher, 2015; Shrout & Bolger, 2002). Here, the product of regres-
sion coefficient, a, the effect of T on M, and, b, the effect of the M on
Y, adjusted for T, is the indirect, mediated effect; coefficient c0 repre-
sents the effect of T on Y, adjusted for M (see Figure 1) and is the
direct effect. In psychology, these coefficients are usually obtained by
estimating two separate ordinary least squares linear regression
models, one for the mediator and one for the outcome, or by estimat-
ing all of them jointly using structural equation modelling (SEM).
While significant advancements in estimation and inferential
techniques have been achieved using the traditional approach
(e.g., Preacher, 2015; Shrout & Bolger, 2002), less emphasis has been
placed on causal assumptions (although, see, e.g., Judd &
Kenny, 1981). A common misconception among researchers is that
randomization of individuals to treatment conditions ensures the
validity of the statistical mediation analysis; it is noteworthy, however,
that it was shown and emphasized early that both direct and indirect
effects do not represent causal quantities (in the same sense as ACE),
even if individuals are randomly assigned to treatment conditions
(Holland, 1988; Judd & Kenny, 1981). Additional assumptions are
always needed, and the CMA movement has been important in clari-
fying the causal assumptions that underpin both the traditional and
modern approaches to mediation (Imai et al., 2010; Jo, 2008).
The potential outcomes framework has been extended to media-
tion, within which potential outcomes can be used to define direct
F I G U R E 1 A conceptual model of mediation showing the
mediated pathway (bolded paths) from the binary treatment variable
(T) to the continuous outcome (Y) via the continuous mediator (M).
The MT variable represents the product of M and T; C is an
unmeasured (latent) confounder influencing both M and Y
4 HESSER
and indirect effects. To define these quantities at the individual level,
we need now also consider the potential outcomes as a function of
the values of the mediator under both treatment and control condi-
tions. In the IBS-trial example, we need to consider the mediator
values for IBS-specific avoidance under the two conditions. Suppose
we use Mi ð1Þ and Mi ð0Þ to indicate potential avoidance mediator
values for individual i under the exposure-based treatment and con-
trol, respectively. As with the potential outcomes, only one of two
potential mediator values is realized. For example, if an individual is
randomized to control, we observe Mi ð0Þ but not Mi ð1Þ. To define
direct and indirect effects, we need to extend our causal model by
considering potential outcomes not only as a function of treatment
but also as a function of both treatment and the mediator values. For-
mally, we define potential outcomes with Y i ðt, mÞ representing the
outcome that would occur if the treatment variable T i and the media-
tor variable Mi had the value t and m, respectively (Imai et al., 2010).
For example, in the IBS-trial, Y i ð1,45Þ represents the level of IBS-
symptoms that would be observed had an individual i been allocated
to treatment and obtained an avoidance score of 45.
Table 1 includes all the potential outcomes combinations for
t = 1 or 0, along with associated causally defined direct and indirect
effects. For example, Y i ð1,Mi ð0ÞÞ refers to the potential value of the
outcome for individual i who is allocated to the treatment but takes
on a value of the mediator that would be realized under the control.
In the IBS-trial, this represents the IBS-symptoms level that would
occur if the individual was in the exposure-based treatment but had
taken the avoidance level that would result under control. Clearly, this
combination of values is impossible to observe in practice as we can-
not observe the mediator value an individual would have taken in con-
trol if, in fact, the individual was assigned to treatment. Thus, these
are purely contrafactual (unobservable) outcomes, but are required for
defining the direct and indirect effects.
Using aforementioned notations, we can then formally define the
indirect effect as Y i ðt, Mi ð1ÞÞ – Y i ðt, Mi ð0ÞÞ for t = 1 or 0 (Imai
et al., 2010). This can be understood as the difference between the
potential value of the outcome under the two conditions where indi-
vidual i with a treatment status of t takes on values for the mediator
of Mi ð1Þ and Mi ð0Þ under the treatment and control, respectively. By
holding constant t, the indirect effect represents the change in the
outcome purely due to a change in mediator values. In the IBS-trial
example, this quantity represents the causal effect on IBS-symptoms
due to the change in avoidance induced by the treatment. The formal
TABLE 1 Casually defined direct and indirect effects based on potential outcomes Y i ðt, mÞ for a binary treatment variable (t = 0 or 1)
Y i ð1, Mi ðtÞÞ
Y i ð1, Mi ð1ÞÞ
Y i ð1, Mi ð0ÞÞ
indirect effect ¼ Y i ðt, Mi ð1ÞÞ – Y i ðt,Mi ð0ÞÞ
TNIE ¼ Y i ð1, Mi ð1ÞÞ – Y i ð1, Mi ð0ÞÞ
Note: PNDE, pure natural direct effect; PNIE, pure natural indirect effect; TNDE, total natural direct effect; TNIE, total natural indirect effect.
definition of the indirect effect captures the following key causal
(counterfactual) question: What change in IBS-symptoms would occur
if one changed the level of avoidance that would be realized under
control condition, Mi ð0Þ, to the level that would be observed under
treatment, Mi ð1Þ, while holding constant treatment assignment at t?
Clearly, when treatment has no effect on avoidance, that is,
Mi ð0Þ ¼ Mi ð1Þ, then the mediated effect is zero. In this way, the defini-
tion formalizes the commonly held intuitive notions about mediation.
Using this definition, there are two indirect effects, one in each
condition: the indirect effect in control (aka. pure natural indirect
effect [PNIE]) and treatment (aka. total natural indirect effect [TNIE]).
When these two differ, we have a non-zero interaction between
treatment and mediator on the outcome (an important point that I will
return to). The same logic applies to the direct effect, which can be
defined as Y i ð1, Mi ðtÞÞ – Y i ð0, Mi ðtÞÞ (Imai et al., 2010). Here, the medi-
ator values, rather than treatment, are held constant. Like the indirect
effects, two direct effects are obtained: the direct effect in control
(aka. pure natural direct effect [PNDE]) and treatment (aka. total natu-
ral direct effect [TNDE]). For t ¼ 1, in the IBS-trial, for example, the
equation represents the effect of exposure-based treatment on an
individual's IBS-symptoms, while holding the level of his or her IBS-
specific avoidance constant at the level that would be realized under
treatment. Importantly, these definitions of direct and indirect effects
also allow us to decompose the total effect (TE) in two ways: TE ¼
TNIE þ PNDE or TE ¼ PNIE þ TNDE: In the continuous case, however,
assuming no mediator by treatment interaction, a single decomposi-
tion of the TE into direct and indirect effects is achieved, since these
quantities do not differ across conditions in such a situation
(i.e., TNIE ¼ PNIE, TNDE ¼ PNDE).
Of course, as with ACE, these causally defined effects are not
possible to estimate at the individual level, and thus, we normally express
all these causal quantities using averages (expectations) as follows:
TNIE ¼ E½Y i ð1, Mi ð1ÞÞ  E½Y i ð1, Mi ð0ÞÞ
PNIE ¼ E½Y i ð0,Mi ð1ÞÞ  E½Y i ð0,Mi ð0ÞÞ
TNDE ¼ E½Y i ð1,Mi ð1ÞÞ  E½Y i ð0,Mi ð1ÞÞ
PNDE ¼ E½Y i ð1,Mi ð0ÞÞ  E½Y i ð0,Mi ð0ÞÞ
TE ¼ E½Y i ð1, Mi ð1ÞÞ  E½Y i ð0, Mi ð0ÞÞ
Y i ð0,Mi ðtÞÞ direct effect ¼ Y i ð1,Mi ðtÞÞ – Y i ð0,Mi ðtÞÞ
Y i ð0, Mi ð1ÞÞ TNDE ¼ Y i ð1, Mi ð1ÞÞ – Y i ð0, Mi ð1ÞÞ
Y i ð0, Mi ð0ÞÞ PNDE ¼ Y i ð1, Mi ð0ÞÞ – Y i ð0, Mi ð0ÞÞ
PNIE ¼ Y i ð0, Mi ð1ÞÞ – Y i ð0, Mi ð0ÞÞ
HESSER
Valeri and VanderWeele (2013) have clarified the four general
assumptions required for providing a causal interpretation of indirect
and direct effects as defined above: (i) no unmeasured treatment-
outcome confounders; (ii) no unmeasured mediator-outcome con-
founders; (iii) no unmeasured treatment-mediator confounders; and
(iv) no measured or unmeasured mediator-outcome confounders
affected by treatment. When treatment conditions are randomized,
assumptions (i) and (iii) are generally satisfied, whereas (ii) and (iv) are
not. The essence of these ideas can also be condensed into a single
assumption, the assumption of sequential ignorability, which is also a
key assumption on which the traditional approach depend (Imai
et al., 2010; Jo, 2008). This assumption, in turn, consists of two igno-
rability assumptions that are assessed sequentially (hence the name).
In addition to assuming that treatment assignment is ignorable (i.e., is
statistically independent of potential outcomes and mediator values),
the assumption states that after adjustment for observed pre-
treatment covariates and observed treatment, assignment of mediator
values is also essentially random (i.e., is ignorable) (Imai et al., 2010). In
the IBS-trial, the randomization of individuals to conditions does not
ensure the second part of the assumption as the posttreatment level
of avoidance is not randomly assigned by the researcher. In other
words, people who decreased their level of avoidance to a significant
amount (i.e., improved) may have different characteristics than those
who did not alter their level of avoidance to the same extent. As a
result, if we are interested in comparing their outcomes, as we are in
mediation analysis, we cannot rule out the possibility that any differ-
ence observed in outcomes is attributable to variations in characteris-
tics rather than differences in mediator values. To satisfy the second
part of the assumption, we need to assume that among IBS-
individuals with the same treatment status and pretreatment charac-
teristics, the mediator values can be regarded as if they were random-
ized. Thus, it is a very strong assumption that need to be recognized
among researchers doing mediation analysis. Is important to note that
even when both treatment assignment and mediator values can be
randomly assigned by the researcher, the sequential ignorability
assumption may still be violated (e.g., in the case of non-zero treat-
ment mediator interaction). In fact, this point is often missed as the
sequential ignorability assumption is sometimes incorrectly inter-
preted as simply the no-admitted variable assumption, and CMA
methodologists have been instrumental in highlighting this essential
aspect (Imai et al., 2010; Valeri & VanderWeele, 2013).
4 | T W O WA Y S CM A C A N I M P R O V E
M E D I A T I ON A N A L Y S I S I N R C T S
CMA appears to be a very different approach to mediation than
the traditional one. However, working with a single continuous
mediator and outcome in an RCT, it can be shown the two approaches
produce the same results and also work under the same causal
assumptions (MacKinnon et al., 2020). In fact, in many cases,
the effects presented within CMA coincide with the effects
of the traditional approach, with some important exceptions
5
(e.g., non-linear models) (Muthén & Asparouhov, 2015). Moreover, in
the case of continuous M and Y, ordinary least squares linear regres-
sion analysis can be used to obtain the unobserved potential out-
comes needed to estimate causally defined direct and indirect effects
(MacKinnon et al., 2020; Valeri & VanderWeele, 2013), so in many
scenarios, there is no need to turn to more advanced methods. This
raises the question of whether CMA brings something new to the
table. In this section, I discuss two data analytical aspects that, I
believe, have been (re-)emphasized as a result of the CMA movement.
4.1 | Consider mediator, outcome confounding
Arguably, and as previously discussed, one of the biggest challenges
with doing mediation analysis in an RCT is that the mediator values
are rarely randomized, and thus, individuals can self-select into differ-
ent values of the mediator (Imai et al., 2010; MacKinnon &
Pirlott, 2015). This opens for unmeasured confounders when we con-
dition on the mediator (in, for example, a regression model). Figure 1
illustrates an unmeasured (latent) mediator-outcome cofounder with
the variable affecting both the mediator and outcome. As stated pre-
viously, while mediator-outcome confounding was highlighted early in
the mediation literature, this is often, incorrectly assumed, to be less
of an issue in an experiment in which individuals are randomized.
Thus, researchers need to be made aware of this issue and carefully
consider mediator-outcome confounding, even in RCTs. Two analyti-
cal aspects are important to consider, both of which have been
highlighted by CMA methodologists. First, researcher interested in
doing mediation analysis need to consider potential (pretreatment)
confounders that are relevant for their study, measure them, and
include them in the analysis as observed covariates (in both the medi-
ator and outcome regression). This requires careful thought in
advance and substantive knowledge in the research area in which the
study is conducted.
Second, given that is unlikely that researchers can identify and
correctly measures all potential confounders in a treatment trial, it is
often recommended that a sensitivity analysis be performed to test
the robustness of the findings to violations to the no mediator-
outcome confounding assumption (Imai et al., 2010;
VanderWeele, 2015). Several sensitivity analyses have been devel-
oped, but one proposed method is to fix the residual correlation
between mediator and outcome at different values to see how this
influences the findings (e.g., indirect effect) (Imai et al., 2010). The
basic idea is that correlation between residuals (assumed to be zero
under sequential ignorability) captures unmeasured confounders that
affect both M and Y (see Figure 1). If the results (e.g., estimate, sign,
and significance) do not change substantially with a high fixed residual
correlation that is taken as evidence for that (unmeasured) con-
founders are unlikely to alter the conclusion. Imai et al. (2010, p. 315)
clarified the overall aim in the following way: “The goal of sensitivity
analysis is to quantify the degree to which the key identification
assumption must be violated for a researcher's original conclusion to
be reversed. If an inference is sensitive, a slight violation of the
6 HESSER
assumption may lead to substantively different conclusions.” They
went on stating that “Given the importance of sequential ignorability,
we argue that a mediation analysis is not complete without a sensitiv-
ity analysis.” This is regrettably rarely done in practice as many
assume that randomization to treatment protects against unmeasured
confounders (see for a recent exception in a clinical trial, Wahlund
et al., 2021).
4.2 | Consider including the mediator by treatment
interaction and examining boundary conditions of the
mediated effect
Another assumption, which is often overlooked in the traditional
approach, is that the association between mediator and outcome
should be homogenous across treatment and control conditions. In
other words, the interaction between treatment and mediator on
outcome should be zero. Using the traditional approach, the
assumption if often assumed, although there may be both substan-
tive and methodological reasons to why this may not be the case
(see Judd & Kenny, 1981; Kraemer et al., 2008; MacKinnon
et al., 2020). As pointed out by VanderWeele (Valeri & the mediator (assessed at later time point). This model may be espe-
VanderWeele, 2013; VanderWeele, 2015), while this interaction was
emphasized early (Judd & Kenny, 1981), it was omitted from one
seminal, widely cited article on mediation (Baron & Kenny, 1986),
possibly leaving many researchers ignorant of this assumption. This
interaction is, however, included in CMA (and corresponds to the
difference between PNIE and TNIE), and mediation effects may be
missed when there is non-zero interaction and the term is not
included in the model (MacKinnon et al., 2020; VanderWeele, 2015).
Figure 1 illustrates the mediator by treatment interaction effect as the
h-path from MT to Y. In this IBS-trial, this would be the effect on IBS-
symptoms due to the interaction term between the post-
measurement of the avoidance variable and the treatment variable. In
other words, with a non-zero interaction, the association between the
mediator, avoidance, and the outcome, IBS-symptoms, differs
depending on which condition you are allocated to. For example, it is
a possibility that by explicitly targeting avoidance in the exposure-
based treatment, it may also change the impact of avoidance on IBS-
symptoms in that condition, whereas the same effect is, however, not
observed in control.
MacKinnon et al. (2020) recently argued that this interaction is
the key link between the traditional approach and CMA, highlighting
the similarities between the two in the continuous case, but also dif-
ferences in interpretation, even when the interaction is included in
the traditional approach. While this key interaction has also been
highlighted outside the CMA literature (i.e., so-called MacArthur
approach to mediation; Kraemer et al., 2008), the CMA framework
allows both direct and indirect effects to be identified and effect
decompositions to be accomplished in the presence of a non-zero
interaction term (Valeri & VanderWeele, 2013). It is, in this context,
important to also note that statistical significance is not an appropri-
ate way of determining whether the interaction should be included in
the model given that most studies have low statistical power of identi-
fying interactions, and non-statistically significant, but non-zero inter-
actions can alter the estimate of the indirect effect (MacKinnon
et al., 2020; VanderWeele, 2015). Thus, a general recommendation is
to include the interaction to examine the impact on the mediated
effect as a sensitivity analysis.
More broadly, researcher should always consider the boundary
conditions for mediated effects. In addition to the mediator by treat-
ment interaction highlighted by CMA methodologists, other theory-
driven interactions are also potentially of importance. The traditional
approach to mediation has also emphasized the key idea of combing
mediation and moderation in informative ways (Hayes, 2017;
Morgan-Lopez & MacKinnon, 2006; Preacher et al., 2007). In fact,
early seminal work made a point of discussing mediation and modera-
tion together (Baron & Kenny, 1986; Judd & Kenny, 1981). Despite
this, potentially important interactions are rarely considered in media-
tion analysis of RCTs evaluating psychological treatments. For exam-
ple, an potentially important conditional process model is the baseline
mediator-by-treatment interaction model (MacKinnon, 2008;
MacKinnon et al., 2007, pp. 606–607). In this model, the baseline
mediator serves as the moderator of the effect of the treatment on
cially important to consider in intervention research as it is reasonable
to assume that mediated effects are stronger for individuals who are
functioning poorly on the mediator at intake due to fact that the
treatment will most likely produce a more pronounced effect on the
mediator in this subpopulation, assuming that the postulated action
theory is correct (Hesser et al., 2018; MacKinnon, 2008; MacKinnon
et al., 2007). In that way, these conditional process analyses not only
provide strong tests of theory, but also clues to whom our theory-
driven interventions are best suited for. Thus, including interactions in
our mediation models, including the treatment-mediator interaction, is
critical to get an in-depth understanding of how, and under what con-
ditions, our treatments work.
5 | C O N C LU D I N G R E M A R K S : W H A T A R E
T H E M O S T S I G N I F I C A N T L E S S O NS LE A R N E D
FR O M CMA ?
For simplicity, I restricted the discussion to continuous variables, but
another essential contribution of CMA has been to formalize effects
that allow for non-linearity and variables with non-normal distribu-
tions, as the formal definitions of direct and indirect effects do not
depend on any specific analytical model (Imai et al., 2010;
VanderWeele, 2015). This makes the overall framework attractive,
and researcher interested in pursuing mediation analysis with, for
example, variables that require non-linear models (e.g., categorical
mediators) would be wise to consider CMA. In fact, CMA is now
implemented in both commercial and noncommercial software
(at least for simpler mediation models; see, for an overview, Valente
et al., 2020), making these methods readily available to intervention
researchers.
HESSER
Clearly, identifying mediators is no simple task as it involves
causal inference with nonexperimental data (even in RCTs). CMA has
made considerable contributions in this regard, and this paper was
written with the aim of clarifying the framework and the key ideas
that are not widely known among clinical psychology researchers. In
addition, I highlighted two specific analytical aspects that are fre-
quently overlooked in the traditional mediation analysis in RCTs eval-
uating psychological treatments. Of course, several formidable
analytical challenges were not covered here, including, but not limited,
to temporal ordering (Tate, 2015), measurements error (Muthén &
Asparouhov, 2015), longitudinal models (Maxwell & Cole, 2007),
multiple mediators and intermediate confounding (De Stavola
et al., 2015)—issues that all require careful consideration and, at the
same time, often complicate identification of causally defined effects.
Furthermore, the greater issue of whether change processes that are
assumed to work at the individual level are reflected in population
parameters at the average (e.g., such as means, variances, and covari-
ances) may require use to turn to person-centred methods for evalu-
ating mediation in psychology (Grice et al., 2015; Hayes et al., 2019).
Yet, this would certainly imply a paradigm shift in how we approach
measurement issues, statistical models, and causal inference in psy-
chology as a whole (Grice, 2015).
In fact, I would suggest that there is no one optimal method to
evaluate mediation, and it is essential to reemphasize the truism that
our models, whether statistical or theoretical, are always wrong, but
may still be useful for practical or theoretical reasons. In this context,
it should also be noted that the sequential ignorability assumption
that was highlighted as one key assumption is not the only assump-
tion available, and other identifying assumptions (e.g., exclusion
restriction) with other types of associated analytical methods
(e.g., principal stratification) may make more sense in certain situations
when working with an intermediate posttreatment variable
(e.g., mediator) linking the independent variable to the dependent
(see, e.g., Hesser, 2020; Jo, 2008; Lynch et al., 2008; MacKinnon &
Pirlott, 2015). Sometimes, it may not be clear which assumption and
method is the best, and researchers may wish to entertain multiple
analytical strategies with different assumptions.
What is clear is that assumptions are always required for causal
inference. The most significant contribution of CMA is the formaliza-
tion of common intuitive ideas about mediation utilizing potential
outcomes—all within a unified causal framework with explicit assump-
tions. These assumptions are, often, difficult to empirically verify, but
by making them explicit, we may at least argue for whether they are
reasonable in a specific situation. Still, one may certainly question if
CMA offers a more solid footing for causal inference. Some scholars
have argued that researchers should only view (statistical) mediation
analysis as an exploratory, descriptive, and hypothesis-generating
method (Kazdin, 2007; Kraemer et al., 2002). On the other hand, by
not discussing causation explicitly—and the assumptions on which
these causal inferences are based—we may be doing ourselves a dis-
service, as others have suggested when it comes to nonexperimental
data in general (Grosz et al., 2020; Hernán, 2018). Causal reasoning
will not go away just because we do not explicitly refer to it by its
7
name and making it explicit may help to improve causal thinking, pro-
cedures, and inference. To cite Kenny (2008, p. 356), “Mediation anal-
ysis is a form of causal analysis. […] all too often persons conducting
mediational analysis either do not realize that they are conducting
causal analyses or they fail to justify the assumptions that they have
made in their casual model.” By demystifying CMA among researchers
in clinical psychology, it is hoped that mediation may be assessed
more rigorously, whether using a traditional or modern analytical
approach, with careful consideration for underlying assumptions. This
paper was written with that aim in mind.
Finally, given the difficulty in identifying mediators by pure statis-
tical means, it is probably wise to consider alternative research
designs whenever possible (e.g., cross-over designs and double ran-
domization) (e.g., Imai et al., 2013) as well as to examine patterns of
findings obtained from multiple studies (patterns matching;
(MacKinnon, 2008). This would most likely require an entire research
program devoted to the study of mediators, which in addition to
appropriate statistical mediation analysis in RCTs also incorporates
fundamental laboratory work and theory development.
AC KNOW LEDG EME NT S
I would like to thank everyone who contributed to the IBS-0 trial,
which was used as an illustrative example.
CONFLIC T OF INT ER E ST
The author declares no conflict of interest.
DATA AVAILABILITY STAT EMEN T
Data sharing is not applicable to this article as no new data were cre-
ated or analysed in this study.
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How to cite this article: Hesser, H. (2021). Identifying causal
mechanisms in psychotherapy: What can we learn from causal
mediation analysis? Clinical Psychology & Psychotherapy, 1–9.
https://doi.org/10.1002/cpp.2687