GORMAN

PSYCHOTHERAPY AND PHARMACOTHERAPY

Combining Psychodynamic Psychotherapy

and Pharmacotherapy

Jack M. Gorman

Abstract: Many patients with depression, anxiety disorders, and other psychiat-
ric disorders are treated with combinations of psychodynamic psychotherapy
and medication. Whether this is better than monotherapy is an empirical ques-
tion that requires much more extensive research than is currently available.
When medications were first introduced to treat psychiatric illnesses, some
psychopharmacologists insisted that it heralded a new area of “biological
psychiatry” that would ultimately render psychotherapy obsolete. Psychody-
namic theorists and practitioners, on the other hand, argued that psychophar-
macology offered only a superficial approach to treatment. Fortunately, these
battles are now largely supplanted by the belief that whatever treatment offers
the patient the best outcome should be employed, regardless of the therapist’s
theoretical outlook. This should motivate more extensive study of the value
of combination treatment. So far, the few studies that have been done suggest
that the combination of psychodynamic psychotherapy and medication may
be superior for the treatment of mood and anxiety disorders, but most of these
studies have small sample sizes and involve only short-term psychotherapy.
An examination of the neuroscience of mood and anxiety disorders and of
the mechanism of action of psychodynamic psychotherapy and of antidepres-
sant medication suggests several routes by which the two treatment modali-
ties could be synergistic: stimulation of hippocampal neurogenesis; epigenetic
regulation of gene expression; dendritic remodeling; enhanced prefrontal cor-
tical control of limbic system activity; and action at specific neurohormonal
and neurotransmitter targets. The evidence for each of these mechanisms is
reviewed with an eye toward potential experiments that might be relevant to
them.

Keywords: psychopharmacology, combination therapy, epigenetics, dendrites,

neurogenesis

Jack M. Gorman, M.D., Franklin Behavioral Health Consultants.

Psychodynamic Psychiatry, 44(2) 183–210, 2016

© 2016 The American Academy of Psychoanalysis and Dynamic Psychiatry
184 GORMAN

Whether the combination of psychodynamic psychotherapy and

pharmacotherapy provides better, worse, or the same outcomes as ei-
ther therapy alone is, of course, an empirical question that can only be
answered by a careful combination of effectiveness and efficacy trials.
Asking the question, however, evokes an interesting set of historical,
clinical, and neurobiological considerations. These include:

• What is the state of the once ferocious divide between the so-called
“biologists” and “therapists” in psychology and psychiatry today?
• Are there any data from properly conducted clinical trials that ad-
dress the issue of combination therapy?
• Is there a neurobiological basis upon which to assume that combi-
nation treatment might be superior (or inferior) to monotherapy?

There is a fairly large body of research exploring whether medication

and cognitive behavioral psychotherapies are synergistic and increas-
ing work documenting that the addition of specific forms of psychoso-
cial intervention may enhance the benefits of pharmacological manage-
ment of schizophrenia and bipolar disorder. Here, however, we will
consider the specific question of adding medication to psychodynamic
psychotherapy for patients with depression and/or anxiety disorders,
the most common psychiatric illnesses in the general population.

Historical Perspective

Medications for the treatment of psychiatric illness were introduced

in the 1950s, when psychodynamic therapy and psychoanalysis were
the predominant modes of intervention. Benzodiazepines proved effec-
tive for anxiety and tricyclic antidepressants (TCAs) and monoamine
oxidase inhibitors (MAOIs) were approved for the treatment of depres-
sion. More than anything else, these developments encouraged some to
believe that psychiatric illnesses were the result of “biological” abnor-
malities like any other medical conditions and therefore that psycho-
analytic notions about the effects of early life trauma and unconscious
conflicts must be incorrect. Since the drugs have well-described effects
on neurotransmitters and their receptors in the central nervous system,
the argument went, their effectiveness must mean that illnesses like de-
pression and anxiety disorders are the result of abnormalities in brain
chemistry, not in emotions.
Debates arose between the two camps in which the proponents of
the new pharmacotherapy argued that psychoanalysis was based on
 PSYCHOTHERAPY AND PHARMACOTHERAPY 185

unproven concepts and lacked any meaningful outcome data. Adher-

ents to psychodynamic therapies countered that the medications fail
to get to the “underlying” problems afflicting psychiatric patients and
offer superficial, quick-fix treatments accompanied by serious adverse
side effects.
Very few psychiatrists or psychologists believe these arguments any
longer. Years of research have failed to tell us much about how exactly
antidepressant medications work and although it is highly likely that
abnormal genes are involved in psychiatric illness, nothing specific has
yet been revealed. Medications no longer seem much of a “quick fix,”
with many patients taking months to find the right medication that
provides adequate symptomatic relief, let alone full remission. On the
other hand, whether psychoanalytic treatments work at a more funda-
mental level than do medications remains a speculation. Hence, a de-
gree of humility has fortunately affected both camps, leading to some
degree of rapprochement. Even 25 years ago Hyland, writing in the
Bulletin of the Menninger Clinic, declared that the “dichotomy between
psychotherapy and pharmacotherapy…has begun to be resolved…”
(1991, p. 205).
Does this mean that the battles about which is better, drugs or thera-
py, are over? Perhaps the overt squabbles have become less trenchant,
but there remain important concerns about the use of medication for
patients who are undergoing psychoanalytic psychotherapies. Psycho-
dynamic thinkers have long advocated for more serious consideration
of the “underlying tension between the dynamic and biologic…and
with the complexity and potential pitfalls that directly and indirectly
affect patient care” (Lee & Hills, 2005, p. 97). Prescribing medication
is noted to have psychological meaning for both the patient (Ramos,
2013) and the analyst (Sandberg, 2014) and to invoke transferential and
countertransferential reactions (Forrest, 2004). Patients wonder if the
therapist who prescribes or refers for prescription of medication has
given up on the therapy. Perhaps the patient has been deemed too ill af-
ter to all benefit from psychotherapy? Therapists may “resort” to medi-
cation when they are angry or frustrated with the patient. Riccio (2011)
even stated that “most of the reasons for medicating patients have to do
with therapist’s unresolved countertransference issues” (p. 338).
Once a pill has been prescribed, the therapist is often obligated to en-
ter into realms of inquiry that might otherwise not occur during a psy-
chodynamic treatment. Now that the patient is supposed to be taking
an antidepressant, his or adherence to it becomes an issue of potential
psychodynamic concern (Alfonso, 2009). There is still the occasional
contention that a psychodynamic perspective is critical to overcoming
“biological reductionism” when medication is prescribed (Vlastelicda,
186 GORMAN

2013). At very least, psychodynamic psychotherapists are advised to

pay careful attention to the meaning of medication to the patient and to
the therapy (Li, 2010; Silvio & Condemarin, 2011).
One interesting area in which psychodynamic therapy and medica-
tion may be combined to superior effect is the treatment of patients
with treatment refractory illness. Mintz and Belnap (2006) coined the
phrase “psychodynamic psychopharmacology” to refer to an approach
that incorporates “a major role for interpersonal and meaning effects”
into the treatment of patients who have failed to respond to medication
management. They argue that “many patients are ‘treatment-resistant’
to medication because an appreciation of the patient’s dynamics is not
incorporated into an understanding of repeated treatment failures” (p.
581). In this regard, it is interesting to note evidence that patients who
receive both medication and psychotherapy seem to suffer with fewer
adverse side effects to medication than do those treated with medi-
cation alone. This was the case in the much discussed comparison of
nefazodone, a cognitive-behavioral analysis system of psychotherapy,
and their combination for the treatment of chronic depression study
(Keller et al., 2000). Similarly, in the collaborative panic disorder study,
patients randomized to receive cognitive behavioral therapy plus imip-
ramine experienced less severe medication adverse side effects; there
were fewer medication-related dropouts compared to those who re-
ceived imipramine alone (Marcus et al., 2007). Psychodynamic prin-
ciples may also help clinicians understand the phenomenon of non-
adherence to medication, which plagues both randomized clinical trials
and everyday pharmacotherapy. As Vlastelica (2013) notes,

Classical psychoanalytic theory, with its emphasis on concepts of resis-

tance, transference, and counter-transference, has shed some light on the
reasons for nonadherence and helped guide clinicians who work with
these patients. Some helpful psychodynamic concepts include a failure of
clinicians to empathize with their patients which is driven from an un-
conscious need to be protected from their distress, and clinicians’ use of
denial, rationalization, and isolation of affect. (p. 317)

Although we are unaware of studies that examine any changes in

attitudes among psychodynamic therapists to the use of medication to
treat anxiety and depression or among psychopharmacologists about
the value of psychotherapy, our impression is that the rancor associated
with debates between the “biologists” and the “psychologists” has sub-
stantially diminished and that practitioners are now willing to accept
the fact that each approach has both advantages and limitations. Those
who approach this area are more likely now to propose ways in which
 PSYCHOTHERAPY AND PHARMACOTHERAPY 187

psychodynamic psychotherapy can enhance psychopharmacology and

vice versa as they are to rail against the “other.” In fact, there appears
to be a growing sentiment that the combination of the two may be su-
perior to either alone, although as we argue in the next section of this
article that idea is also not substantially based on empirical evidence.

Is Combination Therapy Superior to Monotherapy?

If we assume that two treatments work on the same target but neither
is capable of producing a maximum effect on its own or that two treat-
ments affect different targets that are both involved in illness patho-
physiology, then it is reasonable to conjecture that their combination
may be more efficacious that either alone.
There are, of course, many examples of this in medicine. The obvi-
ous ones are situations involving two classes of medication for the
same disease. It is common practice to add a second anti-hypertensive
agent—perhaps a calcium channel blocker—to a first one—perhaps a
diuretic—when initial monotherapy is only partially successful. Either
medication alone is effective in reducing blood pressure, but combin-
ing two mechanisms of action may offer additional benefit. Less often
considered in this context but certainly common is the combination of a
behavioral, lifestyle approach with a medication to treat conditions like
diabetes, hyperlipidemia, or alcohol use disorder. For instance, if diet
and exercise prove insufficient to lower glucose level in a person with
type II diabetes, a hypoglycemic agent is added to the behavioral in-
tervention. A statin may be combined with a low fat diet or naltrexone
with a 12-step program.
If it is the case, then, that psychodynamic psychotherapy and anti-
depressant medications work at different targets and are both effec-
tive, then combining them might offer benefits. It is immediately obvi-
ous, however, that this assertion is based on assumptions that may or
may not be the case. In the next section of this article we will consider
whether it is reasonable to suppose that psychodynamic psychothera-
py and medication in fact work at different targets, but it is certainly
the case that at the present moment we do not in fact know for sure
what the mechanism of action of antidepressant medications actually is
and some would argue that we are equally limited in our understand-
ing of exactly how psychodynamic therapies work. In terms of efficacy,
we have certainly been humbled in recent years with studies showing
that antidepressants, at least in the context of randomized controlled
trials (RCTs), are less effective than we might have once believed. The
STAR*D study, for example, is perhaps most famous for revealing that
188 GORMAN

after an initial course of an SSRI, only about one-third of patients with

depression achieve remission (Trivedi, Rush, Wisniewski et al., 2008). If
two-treatment interventions, regardless of whether they work in differ-
ent ways, have relatively modest efficacy then it is by no means assured
that their combination will improve response.
Hence, it is particularly crucial in the case of combining antidepres-
sants with psychodynamic therapy for depression or anxiety disorders
that RCTs comparing the combination to monotherapy be conducted.
It is worthwhile, therefore, to review some of the work in this area that
has been reported.
There is an extensive literature including numerous well-conduct-
ed RCTs examining the relative advantages of combination therapy
and monotherapies. This has recently been reviewed by Aaronson,
Katzman, and Moster (2015). Depending on which medication, type
of psychotherapy, and disorder is involved the results only occasion-
ally support the idea that combining medication with psychotherapy
is more effective than either treatment alone. These authors concluded
that “For the most part, there is a little evidence that combined psy-
chosocial and medication therapy is superior to either alone in the
treatment of mood and anxiety disorders over time” (p. 538). Most of
the studies tend to show that psychotherapy is at least as effective as
medication and of course has far fewer adverse side effects. Indeed, in
some cases, such as panic disorder, there is evidence that combination
therapy may offer less durable improvement compared to psychother-
apy alone (Barlow, Gorman, Shear, & Woods, 2000). Some caution may
be needed in interpreting these results as a recent analysis claimed that
publication bias—that is, neglecting to publish negative outcome stud-
ies—may have led to an overestimation of the efficacy of psychologi-
cal treatments (Driessen, Hollon, Bockting, Cuijpers, & Turner, 2015).
More important for the discussion here, however, is the fact that al-
most none of the studies involve psychodynamic psychotherapy as an
intervention; most commonly cognitive behavioral therapy (CBT) has
been studied in combination with medication for mood and anxiety
disorders.
Ferrero and colleagues (2007) compared brief Adlerian psychody-
namic psychotherapy to medication and their combination in 87 pa-
tients with generalized anxiety disorder (GAD). There were no statis-
tically significant differences on the main outcome measures among
the three groups, although patients with comorbid personality disor-
ders did better with psychotherapy than medication. Interestingly, at
12-month follow-up, the remission rate among patients in the combina-
tion group based on a Hamilton Anxiety Rating Scale (HAM-A) score
of < 7 was 74% and among patients in the medication arm, 55%; al-
 PSYCHOTHERAPY AND PHARMACOTHERAPY 189

though the difference was not statistically significant, this may be due
to sample size limitations.
In one study, 35 patients with major depressive disorder (MDD) were
treated with either citalopram or paroxetine and randomized to either
brief dynamic therapy or brief supportive therapy for six months, fol-
lowed by six months of medication alone (Maina, Rosso, Crespi, & Bo-
getto, 2007). There were no differences in Hamilton Depression Rating
Scale (HAM-D) scores or other outcome measures at the end of the six
months of randomized treatment, but patients who had been treated
with brief dynamic therapy continued to improve in the six-month
medication only phase, so that at 12 months they had significantly
greater reductions in symptoms compared to those who had received
brief supportive therapy, including a large and statistically significant
advantage in remission rates (75% vs. 12.5%). However, although this
study showed that brief dynamic therapy combined with medication
was superior to brief supportive therapy combined with medication,
it did not adjudicate between combined therapy and psychotherapy
alone.
In a subsequent study, however, the same group (Maina, Roso, & Bo-
getto, 2009) first randomized patients with MDD to a six-month acute
treatment phase of either brief psychodynamic psychotherapy plus
an SSRI (citalopram or paroxetine) or medication alone. There was no
difference in remission rate between the groups (64.1% and 61.4%, re-
spectively). Ninety-two patients who did achieve remission were then
enrolled in continuation treatment with medication alone at the same
dose and then a 48-month follow-up period with no treatment. At the
end of the study, there was a significant advantage for those who had
received combined treatment during the acute phase: 46.9% of the com-
bined group had sustained remission based on HAM-D score criteria at
48 months compared to 27.5% of those who had only received medica-
tion during the acute phase.
The Maina et al. study also suggests that there may be long-term
advantages to psychodynamic therapy that are not necessarily appar-
ent during acute phase treatment. For example, Van et al. (2009) found
that adding medication to the regimen of patients who had not initially
responded to short-term psychodynamic supportive psychotherapy
for depression did not improve outcome, but “it might be warranted
to continue an initially ineffective psychotherapy for depression, be-
cause a considerable number of patients do have a pattern of delayed
response” (p. 205). In at least one analysis of patients with MDD there
is a suggestion that medication plus psychodynamic psychotherapy of-
fered a poorer outcome than psychotherapy alone. Of 53 patients with
depression, anxiety, and/or personality disorders who entered a long-
190 GORMAN

term psychodynamic psychotherapy study, 25 were taking medications

at intake (Bond & Perry, 2006). Being on medication at intake predicted
a smaller effect size for depression and functioning at the seven-year
follow-up. However, as this was not a randomized study it is impossi-
ble to know whether it was the use of medication or some other patient
characteristic associated with taking medication that was responsible
for this finding.
There are a number of other RCTs comparing combined therapy to
medication alone. De Jonghe, Kool, van Aaist, Dekker, and Peen (2001)
randomized 84 patients with depression and a HAM-D score indicat-
ing at least moderate severity to receive antidepressants (fluoxetine,
amitriptyline, or the monoamine oxidase inhibitor moclobemide) ei-
ther alone or in combination with short psychodynamic supportive
psychotherapy. Of note, nearly one-third of the patients refused phar-
macotherapy after randomization, compared to only 13% who refused
combined therapy. Also, almost twice as many patients in the mono-
therapy group stopped medication than did so in the combined group,
once again suggesting that psychotherapy increases antidepressant
medication adherence. Most important, the success rate for combined
therapy (59.2%) at 24 weeks was statistically significantly superior to
monotherapy (40.7%). On the other hand, when the same group (de
Jonghe et al., 2004) later compared short psychodynamic therapy (N =
106) to therapy combined with medication (venlafaxine, an SSRI, nor-
triptyline, or nortriptyline plus lithium) in patients with mild to moder-
ate depression they found the difference in outcome to be “equivocal.”
It may be, therefore, that at least for mild to moderately depressed pa-
tients monotherapy with a psychodynamic approach is as effective as
psychotherapy combined with medication.
In another randomized controlled trial (Burnand, Andreoli, Kolatte,
Venturini, & Rosset, 2002), 74 patients with major depression received
either a combination of the tricyclic antidepressant clomipramine and
psychodynamic psychotherapy or clomipramine alone. Although both
groups experienced significant improvement, the combined treatment
group had fewer treatment failures, better work adjustment, better
global functioning, and a lower rate of hospitalization than the medica-
tion alone group.
An obvious shortcoming of many of these studies, in addition to the
relatively small sample sizes, is that they do not generally address the
effectiveness of psychodynamic psychotherapy as a long-term treat-
ment. More recently, Fonagy and colleagues (2015) used a pragmatic
randomized trial design to study the additive benefit of 18 months of
psychoanalytic psychotherapy for patients with depression who had
not responded to at least two previous treatment attempts, at least one
 PSYCHOTHERAPY AND PHARMACOTHERAPY 191

of which had to include antidepressant medications. Patients were ran-

domized to the long-term psychoanalytic psychotherapy group or to
continue treatment as usual (TAU), which was up to the primary care
provider but did not include psychoanalytic therapy. Both groups were
permitted to receive antidepressants and indeed most of the patients
did take them during the randomized trial. Complete remission was
uncommon in either group and partial remission was not significantly
more likely in the psychotherapy than the TAU group. However, at
follow-up beginning six months after the treatment was completed and
extending for 3.5 years a significantly greater chance of partial remis-
sion in the psychotherapy group emerged. By 42 months after the trial
began, 52.4% of the psychotherapy group patients were in partial re-
mission, compared to 20% of the TAU group patients, a significant dif-
ference. There were no differences between the groups in the number
of prescribed medications. This study suggests that there are long-term
benefits to the combination of medication plus psychoanalytic psycho-
therapy compared to medication plus other forms of psychotherapy.
However, given that the “pragmatic” design used here does not permit
the standardization of treatments it is unclear what relative role medi-
cations, psychoanalytic therapy, and other forms of therapy played in
the outcomes.
Although Silvio and Condemarin (2011) concluded that combination
pharmacotherapy and psychodynamic therapy has become “common
practice” in part because of “efficacy studies that show the superior-
ity of combined therapy over either psychotherapy or medication” (p.
27), the brief review of studies above indicates that there are few de-
finitive studies that make this claim secure. While there are data sug-
gesting that short-term psychodynamic therapy is at least as effective
as other short-term therapies like cognitive behavioral psychotherapy
(Driessen et al., 2013; Fonagy, 2015) and that long-term psychodynam-
ic psychotherapy may be more effective than “less intensive forms of
psychotherapy” (Leichenring & Rabung, 2011; Leichsenring, Abbass,
Luyten, Hilsenroth, & Rabung, 2013), there is clearly a need for studies
documenting one or more of the following: 1. that the combination of
short-term psychodynamic therapy plus antidepressant medication is
superior to both short-term cognitive behavioral or interpersonal thera-
py plus medication and to medication alone in the acute phase of treat-
ing anxiety disorders and depression; 2. that there is a delayed effect
of short-term psychodynamic therapy plus medication that is not seen
with either of the other two approaches; and/or 3. combining long-
term psychodynamic psychotherapy with antidepressant medication
yields better outcomes that short-term approaches to treatment.
192 GORMAN

It might enhance the motivation to initiate such studies, which

would be expensive and lengthy, if we had some at least speculative
neurobiology that could establish a possible basis for the synergy of
psychodynamic therapy and medication. We next turn our attention to
some possibilities.

Is There a Plausible Neurobiology for Combined

Therapy?

From a neurobiological perspective, there are at least two ways that

psychodynamic therapy and antidepressant medication could work to-
gether to produce a better result than either treatment alone, first by
strengthening the same mechanism of action (MOA) and second by
separate MOAs that are synergistic. Exploring these possibilities in
the laboratory would involve at least two types of work: establishing
animal models of the MOA of both treatment modalities and by neu-
roimaging studies in human subjects before and after therapy. Because
to our knowledge no one has yet used either approach to address the
specific question of combination psychodynamic and medication treat-
ment, much of what follows will of necessity be highly speculative.
From the psychoanalytical theory point of view, the MOA of psycho-
dynamic therapy is established, but that does not necessarily translate
into neurobiology. At present we do not know the precise MOA of ei-
ther psychodynamic therapy or antidepressant medication. We will
briefly mention, then, five possible neurobiological scenarios that may
indicate how the combination might work:

1. Stimulation of hippocampal neurogenesis;

2. Epigenetic regulation;
3. Dendritic remodeling;
4. Improvement in prefrontal cortical control over limbic system ac-
tivity; and
5. Alteration in specific hormonal and neurotransmitter systems:
GABA, glutamate, opiate, glucocorticoid, and oxytocin.

Hippocampal Neurogenesis

Until 50 years ago it was held that neurons in the adult mammalian
nervous system are in a permanent post-mitotic phase and therefore
incapable of generating new cells. This explains why spinal cord neu-
 PSYCHOTHERAPY AND PHARMACOTHERAPY 193

rons do not regenerate after injury and brain tumors generally involve
cell types other than neurons. The discovery that neurogenesis does
occur in the brain of mammals throughout the lifespan (Altman & Das,
1965; Bond, Ming, & Song, 2015) stimulated a new area of research that
has burgeoned in the last decade (Ming & Song, 2011). Neurogenesis in
adult mammalian brain occurs mainly in two specific regions, the olfac-
tory bulb and the subgranular zone of the dentate gyrus of the hippo-
campus. Because of the latter’s important role in learning and memory,
it was natural to consider the possibility that a defect in hippocampal
neurogenesis might be involved in psychiatric illness. Indeed, a de-
crease in hippocampal neurogenesis has been posited to play an im-
portant role in both depression and anxiety disorders (Mendes-David,
Hen, Gardier, & David, 2013; Miller & Hen, 2015; Revest et al., 2009).
On theoretical grounds it has been argued that the hippocampal neu-
rogenesis hypothesis cannot explain a complex disorder like depres-
sion in its entirety, since depression appears to involve abnormalities
in vegetative functions and in complex cognitions that are not ascribed
to the hippocampus alone but also to brain regions that do not support
neurogenesis such as prefrontal cortex, amygdala, and ventral striatum
(Gorman & Docherty, 2010). Hippocampal neurogenesis is of course
nearly impossible to measure in humans and even animal models of
depression have not yielded consistent evidence that a defect in hip-
pocampal neurogenesis is a necessary factor.
More persuasive, however, have been findings that antidepressant
medications stimulate hippocampal neurogenesis and that this action
is a critical component of their mechanism of action in treating mood
and anxiety disorders (David et al., 2010; Sahay & Hen, 2007; Warner-
Schmidt & Duman, 2006). At the same time, it is clear from preclinical
studies that stress, a known factor in the etiology of mood and anxiety
disorders, suppresses hippocampal neurogenesis (Mirescu & Gould,
2006; Warner-Schmidt & Duman, 2006), whereas positive experiential
factors, such as exercise, environmental stimulation, and enriched en-
vironments (Kempermann, Brandon, & Gage, 1998; Nilsson, Perfilieva,
Johansson, Orwar, & Eriksson, 1999; Van Praag, Kempermann, & Gage,
1999) enhance neurogenesis. Interestingly, both antidepressant medi-
cation and exercise appear to stimulate neurogenesis at least in part
through interaction with serotonin receptors (Kondo, Nakamura, Ishi-
da, & Shimada, 2015). Hence, to the extent that psychosocial therapies,
like psychodynamic psychotherapy, decrease the response to stressful
situations and create a new, more positive mental environment for the
patient it is plausible that they work at least in part to increase neuro-
genesis. Since hippocampal neurogenesis has also been linked to en-
hanced learning and memory (Deng, Almone, & Gage, 2010), this effect
194 GORMAN

might also explain the ability of psychodynamic psychotherapy to en-

able the patient to use new ways of viewing event and memories in a
more positive way. Thus, it is reasonable to consider the possibility that
medication and psychodynamic psychotherapy might work synergisti-
cally by increasing hippocampal neurogenesis beyond what either is
capable of doing alone.
While there is evidence from a landmark postmortem study that
hippocampal neurogenesis occurs in the human brain (Eriksson et al.,
1998), it is of course not currently possibly to measure neurogenesis
before and after treatment in living humans. Hence, pending the devel-
opment of a highly sensitive neuroimaging technique capable of mea-
suring neurogenesis in humans, any investigation of the neurogenesis
hypothesis must be limited to animal models of mood and anxiety dis-
orders. It would be of interest in this regard if it could be shown that a
combination of antidepressant medication and some form of environ-
mental enrichment, perhaps involving learning, had a greater effect in
enhancing neurogenesis in a rodent than either intervention alone and
that this synergistic effect on neurogenesis correlated with an enhanced
anti-depressant and/or anxiolytic response.

Epigenetic Modification of Gene Expression

Perhaps as revolutionary as neurogenesis in changing our under-

standing of brain function, epigenetics has captured the imagination of
neuroscientists. The sequence of base pairs in the DNA we inherit from
our parents that constitute our genes is mostly immutable throughout
life. This leads to the belief that whatever is in our genome at birth is
fixed and challenges the idea that life experiences can substantially af-
fect molecular processes in the central nervous system. However, it is
now clear that while the physical structure of genes is not altered after
birth, the expression levels of genes are in constant flux.
DNA is wrapped around proteins called histones to form a complex
in the cell nucleus called chromatin. In order for the process of gene
expression to begin with the transcription of DNA to messenger RNA
(mRNA), specific enzymes must make their way into the chromatin
complex. Throughout life, chemical modifications of elements of chro-
matin, such as the addition or subtraction of methyl and acetyl groups,
influence whether a gene can be transcribed and to what degree it is
expressed. Emerging evidence indicates that epigenetic processes like
methylation and acetylation are indeed influenced by the environment;
 PSYCHOTHERAPY AND PHARMACOTHERAPY 195

thus, life experience, both positive and negative, affects the pattern of
gene expression (Nestler, Pena, Kunakovic, Mitchell, & Akbarian, 2015).
Although there are complexities and still-emerging nuances, in gen-
eral methylation suppresses gene expression and acetylation enhances
it. Acetyl groups are removed by the enzyme histone deacetylase and
therefore a class of compounds called histone deacetylase (HDAC) in-
hibitors like sodium butyrate, increase acetylation and in many cases
gene expression. HDAC inhibitors have been shown in numerous pre-
clinical studies to be neuroprotective and to have an antidepressant ef-
fect in animal models of depression. Hence it is possible to affect the
epigenetic status of a gene or genes both by a variety of environmental
interventions and by drugs.
Many animal studies have now shown that early life experience pro-
duces long-lasting changes in DNA methylation and histone acetyla-
tion (Sun, Kennedy, & Nestler, 2013). In a landmark study, Weaver et
al. (2004) found that rat pups with high versus low nurturing mothers
show differences in DNA methylation and histone acetylation begin-
ning in the first week of life and lasting into adulthood. Many of these
changes were reversed by the administration of HDAC inhibitors. In
rats, methylation and demethylation of DNA in the ventral tegmen-
tal area (VTA) of the brain is critical for reward-related memory (Day,
Childs, & Gusman-Karlsson, 2013). In mice, chronic social stress induc-
es long-term demethylation in the region of the gene encoding cortico-
trophin releasing hormone (Crh) and is associated with social avoid-
ance behavior in these mice (Elliot, Ezra-Nevo, Regev, Neufeld-Cohen,
& Chen, 2010). Early life stress causes hypomethylation of the gene en-
coding arginine vasopressin (AVP) protein, leading to persistent over-
expression of the Crh gene (Best & Carey, 2010; Murgatroyd et al., 2009).
There are many more examples of studies that have documented epi-
genetic alterations in response to stress that alter gene expression and
affect the animal’s behavior on a long-term basis.
Although studying epigenetic responses to stress are of course much
more difficult to conduct in humans, studies have shown alterations in
the expression of HDAC genes in blood samples taken from patients
with major depressive disorder and bipolar disorder (Hobara et al.,
2010; Iga et al., 2007). Guintivano et al. (2013) examined DNA methyla-
tion profiles from blood samples of pregnant women with mood disor-
ders and found that subsequent postpartum depression was associated
with DNA methylation changes that were previously associated with
hippocampal synaptic plasticity in rodent models. A genome-wide
methylation study of 94 maltreated and 96 non-traumatized children
196 GORMAN

using saliva samples found that methylation changes in three genes

were associated with depression in the maltreated children (Weder et
al., 2014).
Pharmacological interventions can also affect epigenetic regulation
relevant to emotion and behavior. For example, increasing acetylation
in fear-conditioned mice by administering sodium butyrate enhances
fear extinction (Stafford, Raybuck, Ryabinin, & Lattal, 2012). Histone
deacetylase inhibitors restore contextual memory in a mouse model
of Alzheimer’s disease (Kilgore et al., 2010) and reverse the effects of
chronic social defeat stress (Covington et al., 2009). Fluoxetine reverses
persistent decreases in histone acetylation in the hippocampus that
are caused by chronic social defeat stress in mice (Covington, Vialou,
LaPlant, Ohnishi, & Nestler, 2011). Psychiatric medications, including
antidepressants, produce epigenetic changes in a variety of genes in
several brain areas (Menke & Binder, 2014; Menke, Klengel, & Binder,
2012). It is proposed that the delayed onset of action of antidepressant
medications is due to the time lag in the induction of positive epigen-
etic changes (Vialou, Feng, Robison, & Nestler, 2013).
It is important to note that neurogenesis and epigenetics are not un-
related phenomena. Epigenetic regulation of gene expression plays an
important role in adult neurogenesis (Ma et al., 2010). Thus, further re-
search is needed to determine whether effects of environmental manip-
ulation and psychiatric medications on epigenetic regulations are me-
diated through stimulation of neurogenesis. What is clear, however, is
that at least in animals, exposure to stress at many points in the lifecycle
affects gene expression and that medications reverse many epigenetic
changes caused by adverse life experiences. As would be predicted by
psychoanalytic theory, early life stress induces changes in DNA meth-
ylation and histone acetylation that can persist throughout adult life. It
is also clear that many epigenetic changes are transient and subject to
environmental and pharmacological manipulation. Hence, epigenetic
regulation of gene expression would seem an ideal candidate to explain
the long-lived effects of early childhood adversity on adult behavior
and emotion and be a mechanism by which psychotherapy, medica-
tion, or their combination could reverse pathological epigenetic chang-
es. Given that biomarkers of epigenetic changes have been found in
human patients with mood disorders, it should be possible to develop
studies that test whether psychodynamic psychotherapy affects these
epigenetic indicators and whether there is any evidence that antide-
pressant medication enhances such an effect.
 PSYCHOTHERAPY AND PHARMACOTHERAPY 197

Dendritic Remodeling

Although stimulation of neurogenesis is an attractive hypothesis

for the mechanism of action of both psychotherapy and psychotropic
medication because it is a dynamic, activity-dependent phenomenon,
the fact that it occurs only in the hippocampus in adult brain is a chal-
lenge. Depression and anxiety disorders appear to involve multiple ar-
eas of the brain, including prefrontal cortex and amygdala, in which
neurogenesis does not occur after birth. Another dynamic process in
the brain that does continue robustly throughout life in all parts of the
central nervous system is dendritic remodeling. Gorman and Docherty
(2010) proposed that this should be considered as a candidate explana-
tion for the actions of both psychotherapy and antidepressant medica-
tion.
Axons carrying information from pre-synaptic neurons synapse on
spines located along the axis of dendrites of post-synaptic neurons. A
single neuron may have thousands of spines (Mysore, Tai, & Schuman,
2008). These spines have receptors for neurotransmitters and neuro-
trophic factors on their surfaces. Spines are formed and withdrawn on a
regular basis in response to a wide variety of stimuli (Mysore et al., 2008;
Wyatt, Tring, & Trachenberg, 2012). For example, in the hippocampus
it was shown that the dynamics of dendritic spine turnover matched
the formation and loss of transient memories (Attardo, Fitzgerald, &
Schnitzer, 2015). On the other hand, longer-lived dendritic spines also
support the maintenance of specific long-term memories formed by
different learning experiences (Cichon & Gan, 2015), including memo-
ries that are formed during early life and persist throughout adulthood
(Yang, Pan, & Gan, 2009).
Throughout life, stress and adversity cause the internalization of
dendritic spines and retraction of dendrites themselves (Bluegeot et al.,
2011; Liston et al., 2006; Magarinos, McEwen, Flugge, & Fuchs, 1996).
Conversely, positive experience, such as enhanced early maternal nur-
turing and an enriched environment, cause increased dendritic length,
arborization and dendritic spine surface expression (Champagne et
al., 2008; Galimberti et al., 2006). Antidepressants like fluoxetine have
a similar positive effect on dendrites (Bessa, Ferriera, & Melo, 2009;
Brown, Henning, & Wellman, 2005; Hajszan, MacLusky, & Leranth,
2005; Norrholm & Oimet, 2001). A link with the epigenetic hypothesis is
suggested by the finding that over-expression of a histone deacetylase,
which removes acetyl groups from histones, decreased spine density
and memory formation (Guan et al., 2009).
198 GORMAN

According to the dendritic remodeling theory (Gorman & Docherty,

2010), stress increases the release of the excitatory neurotransmitter
glutamate throughout the brain, which has been shown to play an im-
portant role in destroying dendritic spines (Andres, Regev, Phi, Seese,
Chen, Gall, & Baram, 2013). In excess, glutamate is toxic to neurons and
can cause cell death, an irreversible event in most parts of the central
nervous system. As a protective mechanism, glutamate receptors on
dendritic spines are internalized and dendritic length shortened. While
this may spare neurons from the excitotoxic effects of excessive expo-
sure to glutamate, it also results in a decrease of synaptic connections
within the brain. The inability to integrate new information, make ac-
curate assessments about events and interpersonal relationships and to
control automatic fears and worries are important features of depres-
sion and anxiety disorders and may represent a breakdown in commu-
nication between different brain regions. Loss of synaptic connections
because of stress-induced dendritic remodeling may represent a cel-
lular and molecular mechanism that effectively impairs normal com-
munication within the brain. Indeed, in an elegant study Dias-Ferreira
et al. (2009) showed that chronic stress-induced dendritic atrophy in
rats was associated with behavioral changes highly reminiscent of
depressed humans, such as an inability to perform actions and make
choices based on consequences, and a bias to behave out of habit.
Because increased dendritic branching and spine expression, like
neurogenesis and epigenetic regulation, are stimulated by both positive
environmental influences and antidepressant medications, dendritic re-
modeling is thus another way in which psychodynamic psychotherapy
and medication might collaborate.
Once again, evaluating the impact of any treatment intervention on
dendritic architecture in human subjects will be difficult. There are a
few postmortem studies showing decreased dendrite and spine densi-
ties in people who had high levels of trait anxiety and depression scores
during life (Soetanto et al., 2010). There is evidence, however, that short-
term interventions such as two weeks of daily reading practice, which
activates multiple brain areas, is accompanied by an increase in gray
matter volume in the occipital cortex (Ilg, Wohlschläger, Gaser, Liebau,
Dauner, Wöller et al., 2008). The authors speculated that this structural
change was due to synaptic remodeling. It is conceivable, therefore,
that volumetric MRI studies could demonstrate increased gray matter
volume that is greater in patients receiving combination psychotherapy
and medication than either alone, and is attributed to an enhancement
in dendritic length and arborization.
 PSYCHOTHERAPY AND PHARMACOTHERAPY 199

Strengthening Cortical Control Over Limbic Structures

The three areas for possible psychotherapy/medication synergy

mentioned so far all involve molecular and cellular processes. On a
neurocircuitry level, a great deal of interest has been generated around
the idea that mood and anxiety disorders involve a disruption of the
normal relationship between the prefrontal cortex (PFC) and limbic
structures such as the amygdala. Among many aspects of this relation-
ship is mutual inhibition whereby amygdala activation reduces PFC
activity and vice versa. The amygdala is activated by both positive and
negative strong emotional cues and has been most often linked in the
preclinical and clinical literature to the initial processing of fear stimuli.
In the laboratory, an intact amygdala is necessary for conditioned fear to
occur. Amygdala activation under conditions of significant fear inhib-
its activity in the PFC (Garcia, Vouimba, Baudry, & Thompson, 1999).
On the other hand, the extinction of conditioned fear requires activity
in an inhibitory pathway from the medial PFC (mPFC) to the amyg-
dala (Quirk, Garcia, & Gonzalez-Lima, 2006) and mPFC activation im-
pairs amygdala function (Berkowitz, Coplan, Reddy, & Gorman, 2007;
Quirk, Likhtik, Pelletier, & Pare, 2003). It is reasonable to summarize
the laboratory findings as representing the ability of a primitive fear
response located in the amygdala to inhibit a reasoned response by the
PFC and, conversely, the ability of logic and rational assessment located
in the PFC to suppress primitive fear originating in the limbic cortex.
Functional imaging studies of human subjects have shown that stron-
ger connectivity between amygdala and mPFC is associated with re-
duced anxiety (Kim & Whalen, 2009; Kim et al., 2011; Phelps, Delgado,
Nearing, & LeDoux, 2004). There is substantial evidence that patients
suffering from anxiety and/or depression manifest a decrease in connec-
tivity between the amygdala and the PFC (Moses-Kolko et al., 2010; for
a review, see Gorman & Nathan, 2015). Furthermore, there is evidence
that successful antidepressant treatment normalizes amygdala function
and restores PFC to amygdala connectivity (Gorman & Nathan, 2015;
Ruhe, Booji, Veltman, Michel, & Schene, 2012). Interestingly, this could
be an area in which medication and psychotherapy are not synergistic
but rather that medication interferes with psychotherapy. In animals,
the SSRI citalopram reduces conditioned fear response (Burghardt et
al., 2004) but also inhibits fear extinction learning (Burghardt, Sigurds-
son, Gorman, McEwen, & LeDoux, 2013). Similarly, one study of panic
200 GORMAN

disorder patients found that while antidepressant medication, cogni-

tive behavioral therapy, and their combination worked equally well for
acute treatment, patients who received medication alone or the com-
bination of medication and psychotherapy did less well on long-term
follow-up than those treated with psychotherapy alone (Barlow et al.,
2000). It has been suggested that medication inhibits learning necessary
to extinguish and benefit from cognitive behavioral therapy. Whether
this is also the case with respect to psychodynamic psychotherapy is
not yet known.
Gorman and Roose (2011) speculated that psychodynamic psycho-
therapy affects the reconsolidation of recovered fear memories. In ro-
dents, reactivation of a conditioned fear memory results in a period
of lability, during which the memory can be altered or even abolished
before being reconsolidated into long-term, permanent memory. By
analogy, Gorman and Roose argued, one mechanism by which psycho-
dynamic psychotherapy may work is to make unconscious conflicts
conscious and then alter them through interpretation, thereby turning
them into less harmful memories before reconsolidation back into un-
conscious memory. This theory locates at least one aspect of psycho-
dynamic psychotherapy firmly in the neurocircuitry that involves the
amygdala and PFC and therefore begs the question of whether another
important aspect of psychodynamic psychotherapy is to strengthen
PFC to amygdala connectivity. We already have tools to investigate this
possibility: functional magnetic imaging and positron emission tomog-
raphy imaging can be used to study activity in the amygdala and PFC
and the strength of their connections both before and after medication,
psychotherapy, and their combination. Although such a study would
be highly complex, it would go a long way to elucidating how these
therapies might be working both alone and in combination.

Neurotransmitter Function

Although as stated earlier it is now clear that depression and anxiety

disorders cannot be explained by simple overabundance or deficiency
of serotonin or norepinephrine as was held for so many years, this of
course does not mean that abnormal neurotransmitter function lacks
an important role in the pathophysiology of anxiety and depression.
While a thorough review of all of the possible neurotransmitter loci
that might be affected by a combination of pharmacotherapy and psy-
chodynamic psychotherapy is beyond the scope of this article, we will
touch on a few of them.
 PSYCHOTHERAPY AND PHARMACOTHERAPY 201

There is currently great interest in and anticipation for the introduc-

tion of the glutamate receptor antagonist ketamine as a treatment for
depression. Based on the idea that excessive glutamate neurotransmis-
sion may play an important role in the etiology of depression, it has
been shown in multiple studies that ketamine administration confers
rapid amelioration of depression (Iadarola et al., 2015). A type of glu-
tamate receptor, the NMDA receptor, has been shown to be sensitive to
the effect of stress (Ganguly, Holland, & Brenhouse, 2015; Wang, Yang,
Dong, Cau, & Xu, 2006) and the NMDA receptor is involved in hip-
pocampal neurogenesis (Nacher & McEwen, 2006). NMDA receptor
antagonists can reverse the behavioral and synaptic effects of chronic
stress (Li et al., 2011). Once again, a system that is responsive to stress
and to pharmacotherapy may be one that is also responsive to psy-
chodynamic psychotherapy aimed at relieving the effects of early life
trauma.
Another neurotransmitter system that could serve both psychody-
namic psychotherapy and medication effects is the neurohormone
oxytocin. Activation of brain regions rich in oxytocin and oxytocin re-
ceptors are clearly involved in attachment behavior and possibly ro-
mantic love (Zeki, 2007). Oxytocin neurotransmission is involved in
stress regulation and social behavior in animals and humans (Feldman,
Monakhov, Pratt, & Ebstein, 2015) and may play a role in depression
(McQuaid, McInnis, Abizaid, & Anisman, 2014). Numerous clinical tri-
als with oxytocin analogues and agonists have been conducted for the
treatment of a wide variety of psychiatric disorders, some of which have
yielded positive results (Bakemans-Kranenburg & IJzendoorn, 2013). A
system so important in the development of trust, attachment, and af-
filiation may very well be one that is activated by establishing positive
transferential relationships with a psychotherapist. It seems very likely,
therefore, that psychodynamic psychotherapy has effects on oxytocin
pathways in the brain. If oxytocin-like drugs are discovered that are
therapeutic, a psychotherapy/medication combination might be even
more effective.
Similar speculations can be made about numerous other neurotrans-
mitter systems that are emerging as potential therapeutic targets, in-
cluding those involving orexin, opioids, and CRH. It must be remem-
bered, however, that simple tests of levels of neurotransmitters in blood
or CSF are unlikely to generate sufficient useful information regarding
the effectiveness of any treatment for anxiety disorder or depression.
Hence, only clinical trials studying the effects of both monotherapy and
combination treatments will be helpful at the present time.
202 GORMAN

Conclusions

The disciplines of psychiatry and psychology are clearly open to the

possibility that combining pharmacotherapy and psychotherapy may
be more helpful than either treatment alone for some patients. So far,
we have only a limited number of suggestive studies that validate the
idea that combined medication and psychodynamic psychotherapy
may specifically work for patients with depression and anxiety disor-
ders. There is no question that for this idea to be taken seriously, more
extensive clinical trials are required. An impetus to do this work comes
from the substantial amount of neuroscience that provides a theoreti-
cal basis for the synergy of medication and psychodynamic psycho-
therapy. Most of this evidence comes from preclinical studies and it will
be admittedly difficult in many instances to adjudicate the validity of
these animal studies in living humans. Nevertheless, preclinical studies
are now being used as theoretical supports for the development of psy-
chiatric interventions, such as glutamate antagonists for depression.
Perhaps they will give added encouragement to the study of combina-
tion treatments as well.
There is a mistaken notion in many sectors that brain research ap-
plies only to psychopharmacology whereas psychotherapy is the do-
main of an ineffable concept called “mind.” As Eric Kandel has repeat-
edly pointed out, however, “the brain is the organ of the mind” (Weir,
2012). All of life’s experiences, including those that occur during psy-
chotherapy, are received and interpreted by neural circuits and the ma-
chinery for these circuits are activated genes and proteins within the
brain. This is not reductive by any means; the brain is the most complex
entity in the universe and the complicated array of gene activation, epi-
genetic regulation, and dendritic remodeling mentioned in this article
are only a few of the many ways in which our brains respond to the
environment; make, store, and reactivate memories; and formulate de-
cisions and plans of action. Modern neuroscience has already helped
us understand how unconscious mental processes work and how early
life adversity affects adult behavior and emotion. This work forms the
basis for a neurobiology of psychodynamic theory and therapy.
Because psychodynamic psychotherapy is a powerful intervention
it by definition must have potent effects on the molecular, cellular, and
systems biology of the central nervous system. Deciding whether it can
work in concert with medications, agents that have perhaps more ob-
vious but also more limited effects on molecular targets than psycho-
therapy, requires the use of clinical trials technology and neuroscience
investigation. It remains an open question as to whether the combi-
 PSYCHOTHERAPY AND PHARMACOTHERAPY 203

nation is better than monotherapy and if it is for which illnesses and

specific patients. We are privileged to work in a climate today in which
collaboration among many types of scientists, including those versed
in pharmacotherapy and psychodynamic psychotherapy, are both pos-
sible and potentially highly meaningful.

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