2012. Vol.3, No.10, 857-863
Published Online October 2012 in SciRes (http://www.SciRP.org/journal/psych) http://dx.doi.org/10.4236/psych.2012.310129
Copyright © 2012 SciRes. 857
The Biological Effects of Psychotherapy in Major Depressive
Disorders: A Review of Neuroimaging Studies
Gülfizar Sözeri-Varma, Filiz Karadağ
Department of Psychiatry, Faculty of Medicine, Pamukkale University, Denizli, Turkey
Received July 21st, 2012; revised August 25th, 2012; accepted September 27th, 2012
Major depressive disorder (MDD) is a syndrome, which is quite frequent in the society, can be recurrent
and shows symptoms of emotional, cognitive and behavioral disorder. Brain imaging studies support that
patients diagnosed with MDD suffer dysfunction in limbic structures such as frontal cortex, amygdala,
hippocampus and cingulate cortex and basal ganglions that regulate these functions. Psychotherapy is an
effective treatment option for prevention of recurrent depressive attacks as well as for acute treatment of
depression. It is thought that psychotherapy shows its effect by focusing on misleading cognitions and
emotional information processing processes that lead to rise and persistence of symptoms of depression,
which in turn boosts problem solving and coping skills. Neurobiological reflections of clinical recovery
achieved by psychotherapy are not yet well known. In this study, it is aimed to review cognitive behav-
ioral psychotherapy (CBT), interpersonal psychotherapy (IPT) and psychodynamic psychotherapy meth-
ods used frequently in treatment of MDD, along with functional brain imaging studies performed on
treated depressive patients. Studies show that CBT lead to changes in the prefrontal cortex, cingulate cor-
tex and amygdala metabolisms and activities. Activity of the subgenual cingulate cortex, which takes part
in the regulation of the limbic activity, seems to play an important role in the response to CBT like in the
response to antidepressant treatment. It was found that interpersonal psychotherapy (IPT) ensures recov-
ery of metabolism and blood flow in the prefrontal cortex, cingulate cortex and basal ganglions. It was
observed that psychodynamic therapy ensured recovery of abnormal activities in especially the prefrontal
cortex and cingulate cortex in MDD, similar to the CBT and IPT. There is need for more long-term, fol-
low-up studies in this area.
Keywords: Depression; Psychotherapy; Cognitive Behavior Psychotherapy; Interpersonal Psychotherapy;
Psychodynamic Psychotherapy; Neurobiology
Major Depressive Disorder
Major depressive disorder (MDD) is a syndrome widely seen
in the population that subverts functionality of the individual
and affects his/her life negatively, with basic symptoms of de-
pressed mood, loss of interest and desire, along with anhedonia.
Symptoms of MDD can be summarized in 3 main domains. In
the mental-behavioral domain, it is possible to see loss of
meaning of life with emotions of desperateness, unworthiness,
seeing oneself inferior and retardation in thoughts and behave-
iors in addition to these main symptoms. It is possible to see
anxiety and tension, suicidal thoughts and attempts. In the cog-
nitive domain, it is possible to see a decline in the capacity to
focus thoughts on a topic, insufficiency of intellectual functions
and problems in memory areas in particular. Seeing past deeds
and achievements worthless and meaningless, self-accusation,
pessimism, hopelessness are other frequent symptoms. In the
physical domain, possible symptoms are loss of energy and
fatigue, change in appetite, sleep disturbances, decline in sexual
interest and desires, somatics symptoms such as headaches and
back pains (Güleç, 2003; APA, 2005).
Neurobiology of Major Depressive Disorder
Disturbances in neurotransmitters such as noradrenalin and
dopamine, neuroendocrine disturbances, circadian arrhythmia,
genetic factors, and serotoninergic dysfunction in particular,
play a role in MDD etiopathogenesis (Yüksel, 2003; Holtz-
heimer & Mayberg, 2008).
Dysfunction of prefrontal cortex (PFC) and striatal structures
that regulate the limbic system and the brain stem lies beneath
the depressive symptoms. It is reported that volume changes
occur in the PFC, hippocampus and striatum (Hastings et al.,
2004; Zou et al., 2010; Malykhin et al., 2011), neurons and
glias get damaged, number and dimensions of the neurons di-
minish (Rajkowska et al., 1999; Oh et al., 2011), and frontal
hypoperfusion occurs (Drevets, 2000; Narita et al. 2004) in
MDD. Lorenzetti and colleagues (2009) reviewed structural
magnetic resonance imaging (MRI) studies that were conducted
between 2002 and 2007. The authors found that reduction of
volume in hippocampus, basal ganglia and PFC is a consistent
finding in MDD. Especially, it was found that in patients, who
suffer the disorder for a long time with recurrent episodes, re-
gional brain volume has considerably been affected.
Phenomenological differences between patients with mood
disorders is explained by the hypothesis of dysfunction between
neural cycles, which is defined as the putative neural network
model of mood disorder. This hypothesis is based on presence
of functional disorder between neural networks in mood disor-
ders. As a response to these dysfunctions, compensatory mecha-
nisms appear in neuronal networks. Compensatory mechanisms
G. SÖZERI-VARMA, F. KARADAĞ
may cause changes in the neuronal network that result in dif-
ferent symptoms. Disturbances in the limbic-thalamo-cortical
cycle and limbic-cortical-striatal-pallidal-thalamic cycles that
also cover these cycle, or in more general terms rise and/or
decline in some synaptic activities in these structures is thought
to be responsible for etiopathogenesis of MDD. It is pointed out
that most consistent finding obtained from functional neuroi-
maging studies in patients with MDD is the decline in the fron-
tal lobe functions. In MDD, there is an inverse relationship
between the prefrontal activity and severity of depression dur-
ing resting period. It is assumed that metabolic changes that
take place are the lesion itself or an ongoing self-recovery at-
tempt. For example, frontal hyperactivity may be an exagger-
ated or unsuitable compensatory process that results in psy-
chomotor agitation or ruminative thoughts; and it may result in
persistence of the negative mood by causing abnormal chronic
activity of the limbic-subcortical structures. Frontal hypome-
tabolism might be a result of insufficiency information or con-
tinuation of compensatory mechanisms that result in apathy,
psychomotor retardation and disturbance of driving functions.
Complete identification of contributions of adaptive and mal-
adaptive compensatory responses may enable choice of optimal
therapy option by taking different effects of different therapeu-
tic methods into consideration (Drevetes, 1998; Mayberg, 2006;
Holtzheimer & Mayberg, 2008).
There are psychotherapy methods, whose effectiveness on
depression is proved by research, and which has model-specific
formulations and attaches importance to psycho-education and
use according to guides. Most widely used of these are cogni-
tive-behavioral psychotherapy, interpersonal psychotherapy and
short-term psychodynamic psychotherapy. Common features of
these methods are short-dated treatment protocols that last 2 to
4 months, ability to observe and measure the decline in the
symptoms, and unique theoretical basis of each of the models
(Driessen ve ark., 2007, Friedman ve Thase, 2009). For this
reason, mentioned psychotherapy methods are thought to be
suitable tools to research the brain activity changes that ac-
company depression therapy.
In this study, it is aimed to review the neurobiological effects
of psychotherapies in unipolar major depressive disorder. Lit-
erature search revealed that studies in this field focus on appli-
cations of cognitive-behavioral psychotherapy, interpersonal
psychotherapy and psychodynamic psychotherapy. Since re-
search in this field is limited, all articles that could be accessed
are included in the study.
Cognitive Behavioral Psychotherapy and
Cognitive behavioral psychotherapy (CBT) received most
attention in the studies that deal with neurobiological effects of
psychotherapies in MDD. CBT is an effective psychotherapy
method commonly used for treatment of depression. According
to CBT, maladaptive information processing processes, such as
misleading beliefs and recurrent negative thoughts, over-gen-
eralization, over-personalization, selective abstraction, thought
of all-or-nothing, lie under depression (Beck, 2005). In MDD, it
is found that maladaptive cognitive processes such as rumina-
tions and strongly negative self-focus is connected to hyperac-
tivity of PFC and rostral anterior cingulate cortex (ACC) (Yo-
shimura, 2010). It is detected that while emotional decisions are
made by depression patients, there is hypoactivity in the left
and hyperactivity in the right of the dorsolateral prefrontal cor-
tex (DLPFC) (Grimm, 2008). It is found that effective connec-
tions between PFC, ACC and amygdala got disturbed in pa-
tients with MDD. Regulative effect of PFC on amygdala be-
comes insufficient and bottom to up activity increases in the
connections between amygdala and ACC, and between ACC
and PFC. It is claimed that in MDD, reason behind the diffi-
culty in coping with emotional stimuli is the breach of the con-
nection between the prefrontal cortex and amygdala (Siegla
2007; Moses-Kolko, 2010; Carballedo, 2011; Lu, 2012).
Neurobiological effects of CBT were observed using func-
tional imaging techniques (positron emission tomography scan-
ning/PET and functional magnetic resonance imaging/fMRI)
(Table 1). Goldapple and colleagues (2004) studies all brain
metabolisms before and after the treatment with PET and com-
pared psychotherapy and pharmacotherapy. In both treatment
groups, similar levels of recovery were observed in the severity
of the depression. In the psychotherapy group, hippocampus
and dorsal cingulate metabolisms increased and PFC metabo-
lism decreased in the direction of normalization. In the phar-
macotherapy group, exactly opposite changes were observed as
prefrontal activity increased and hippocampus and cingulate
activity decreased. It was commented that there may be a rela-
tionship between the decline in ruminative thoughts and other
dysfunctional thoughts achieved by psychotherapy and the
decline in the PFC activity; and pharmacotherapy ensured re-
pression of limbic activities and regulation of emotional reac-
tivity. In a similar study, 12 patients diagnosed with MDD were
applied CBT and 12 patients were applied venlafaxine treat-
ment. After a treatment period of sixteen weeks, changes in
brain metabolism were investigated by PET. In both treatment
groups, it was found that orbitofrontal cortex and left medial
PFC metabolisms decreased and right occipital-temporal cortex
metabolism increased. Difference was detected in terms of
effects on subgenual cingulate and caudate in the two treatment
groups. It was concluded that subgenual cingulate might have
an important role in response to the treatment (Kennedy et al.,
Cingulate cortex plays an important role in depression ther-
apy. In a study, hypermetabolism was detected on the interface
between pre-treatment pregenual and subgenual cingulate cor-
tex in the patients who did not respond to psychotherapy and
venlafaxine treatment. However, hypometabolism was detected
in the same region in the patients who responded to the treat-
ment. It was argued that hyperactivity in the subgenual cingu-
late cortex might be an indication of resistance to both psycho-
therapies and pharmacotherapy (Konarski, 2009). A meta-
analysis study showed that changes in the frontal and cingulate
cortex metabolisms are consistent findings. To a lesser extent,
changes in other limbic and sub-cortical regions (hippocampus,
amygdala, posterior cingulate, striatum and thalamus) were
reported. Frontal and cingulate cortex are divided into different
regions according to anatomical, functional, structural and post-
mortem studies: dorsolateral and ventromedial prefrontal cortex,
dorsomedial and ventrolateral prefrontal cortex, dorsomedial
and ventromedial frontal cortex; dorsal, rostral, subgenual cin-
gulate. It was found that pharmacological, cognitive and so-
matic therapies cause different changes in different regions of
the prefrontal and cingulate cortex (Seminowicz et al., 2004).
In some studies, neurobiological effects of psychotherapies
were investigated using functional Magnetic Resonance Imag-
ing (fMRI) method. It has been determined that in major
Copyright © 2012 SciRes.
G. SÖZERI-VARMA, F. KARADAĞ
Copyright © 2012 SciRes. 859
The studies of cognitive behaviour psychotherapy.
Study Subjects, t herapy, duration of
therapy Imaging Results
Goldapple and colleagues
CBT, n: 17, 15 - 20 seans
paroksetine-treatment, n: 13
Decrease d metabolism
Dorsal, ventral, medial frontal cortex
Hippocampus, dorsal cingulate
Decrease d metabolism
Hippocampal, subgenual cingulate
Kennedy and colleagues
CBT, n: 12
venlafaksine-treatment, n: 12
Both CBT and venlafaxine responders
Decrease d metabolism
Bilaterally orbitofrontal cortex, left dorsomedial
Right inferior occipital cortex
Konarski and colleagues
CBT, n: 17
venlafaksine-treatment, n: 14
Nonrespond ers to CBT or venlafaksine,
Hypermetabolism interface of the pregenual and
subgenual cingulate cortices
Siegle and colleagues
CBT, n: 14
healthy control, n: 21
CBT respond ers
Decreased re activity
Subgenual cingulate cortex
Increased rea ctivity
Fu and colleagues
CBT, n: 16
healthy control, n: 16
Elevate amygdala activity and anterior cingulate activity
may be a predictor of treatment response to both
pharmacotherapy and CBT
Costafreda and colleagues
CBT, n: 16 fMRI/emotional stimuli Anterior cingulated cortex activity may be predictor of
the response to pharmacotherapy and CBT
CBT, n: 22
healthy control, n: 14
Prior to treatment, in MDD
Reduce activity in the PFC,
diminishe discrimination between emotional and neutral
items in the amygdala, caudate, and hippocampus
Overall increase in PFC activation, enhanced arousal
responses in the amygdala, caudate, and hippocampus
Note: MDD: Major depressive disorder; CBT: Cognitive Behaviour Psychotherapy; PFC: prefrontal cortex; PET: Positron emission tomography scanning; fMRI:
Functional magnetic resonance imaging.
depressive disorder there is a general decrease of activity in the
ventromedial prefrontal cortex (PFC); that the distinction of
emotional and neutral stimuli in amygdala, caudate, hippocam-
pus decreases and that the response to negative stimuli in left
anterior temporal lobe and right dorsolateral PFC in comparison
to positive stimuli. Following CBT, MDD patients exhibited
overall increases in ventromedial PFC activation, enhanced
arousal responses in the amygdala, caudate, and hippocampus,
and a reversal of valence effects in the left anterior temporal
lobe (Ritchey et al., 2011). Fourteen patients with MDD and 21
healthy control subjects were compared in terms of activity
during emotional response. It was found that in patients with
MDD, both subgenual cingulate cortex and amygdala showed
abnormal activity. Strong relationship was found between low
reactivity in subgenual cingulate cortex, high reactivity in
amygdala and the response to CBT. Decline in subgenual cin-
gulate cortex activity before the therapy is a predictor for re-
sponse to CBT and shows a deficit in regulation of this area. It
is argued that CBT might be providing recovery by fixing the
disturbances in the emotional regulation (Siegle et al., 2006).
ACC is the first piece of the Papez circuit that is known to be
associated with regulation of emotions. It is known that in de-
pression patients, grey matter volume, blood flow and glucose
metabolism decrease in the subgenual cingulate cortex (Drevets,
2008). Data at hand shows that cingulate cortex functions that
get disturbed in MDD might be recovered by CBT.
The other study, patients with MDD, healthy individuals
with cognitive vulnerability to depressive disorder and healthy
control group were compared. In patients with MDD, it was
found that amygdala response increased and DLPFC response
decreased during emotional matching task compared to the
healthy control group. Similarly, when the group with cognitive
vulnerability was compared to the healthy control group, it was
found that bilateral amygdala activity was higher and bilateral
G. SÖZERI-VARMA, F. KARADAĞ
DLPFC activity was lower. These findings show that response
to an emotional stimulus in depression may be in the form of
hypoactivation of the prefrontal cortex and hyperactivation of
amygdala. It is pointed out that they indicate a disorder in cog-
nitive regulation of emotions by neural network in individuals
with cognitive vulnerability to depression (Zhong, 2011). Con-
tinuous activity of amygdala was found to be more related to
the intensity of the ruminative thoughts than to the severity of
depression. It is asserted that continuous high reactivity of
amygdala and continuous low reactivity of subgenual cingulate
cortex reflect as ruminations on the clinic (Siegle et al., 2007).
Fu and colleagues (2008) reported that amygdala-hippocampus
activity is relatively high compared to the healthy group during
depressive episode and there is a correlation between the basal
ACC activity and the response to the therapy. A similar study
supports that in depression neural network that contains ACC is
important for response to the CBT, and that changes in the
ACC activity may be predictor of the response to pharmaco-
therapy and CBT (Costafreda et al., 2009). CBT possibly shows
its effect more controlled information processing processes
replace emotional responses, automatic limbic reactions are
prevented and role of inhibitor driving mechanisms increases
(Derubeus, 2008; Holtzheimer &Mayberg, 2008).
Findings derived from these studies show that CBT ensures
recovery in the maladaptive information processing processes
in MDD by causing changes in the PFC, ACC, and amygdala
metabolisms. There are clues that metabolism and activity
changes in the cingulate cortex (especially in the subgenual
area) might be decisive on response to the therapy.
Interpersonal Psychotherapy and Neurobiology
Interpersonal psychotherapy (IPT) aims to alleviate depres-
sion by raising quality of interpersonal world of the patient.
Phenomenological formulation of this method is based on so-
cial environment of the individual. Depression is associated
with current interpersonal relationship problems. The patient is
assisted to gain social skills so that she/he can solve his/her
interpersonal relationships. In IPT, 12 to16-week sessions are
applied and 4 main topics are focused on: 1) Unresolved Grief:
The patient is encouraged to mourn after the relative lost and
establish new relationships; 2) Role conflict: In case of social
role conflict, the individual is encouraged to reevaluate the
difficulties and search for ways of solution; 3) Role transitions:
Possible gains for the patient from role transitions are worked
on; 4) Interpersonal deficiencies: When interpersonal conflicts
are evident, psychotherapy aims at overcoming social isolation.
Another characteristic of this method is supporting of strong
aspects of the patient (Alkan, 2007; Friedman & Thase, 2009).
Three studies done in this area has been reached (Table 2). A
study conducted by Brodly and colleagues (2001a) compared
brain metabolism of 24 patients suffering major depressive
disorder with a healthy control group of 16 people (using PET).
Ten patients with depression were applied paroxetine and 14
patients were applied IPT. Patients who had MDD before the
treatment had PFC, caudate and thalamus metabolisms higher
than and temporal lobe metabolism lower than the control
group. In both groups, PFC (bilateral in the group taking par-
oxetine and right in the group receiving IPT) and left anterior
cingulate gyrus metabolisms decreased and left temporal lobe
metabolism increased to return to normal. In the other study of
the same author, metabolic values of 14 patients who were
applied IPT for 12 weeks were compared to 24 patients who
took paroxetine. Correlation was found between recovery from
anxiety, psychomotor retardation, tension and fatigue symp-
toms and the decline in the ventral frontal lobe metabolism;
between recovery from anxiety and tension symptoms and the
decline in ventral anterior cingulate gyrus and anterior insula
activity; between psychomotor retardation and the increase of
dorsal anterior cingulate activity; and between cognitive dis-
turbance and the increase of DLPFC metabolism. It was con-
cluded that findings supported limbic-cortical dysregulation
theory in MDD, metabolic changes occurred in the frontal zone
in depression and IPT fixed these (Brody et al., 2001b).
In another study, 13 patients diagnosed with MDD and suffer
medium to severe depression were applied IPT and 15 patients
were applied 75 mg/g venlafaxine. After 6 weeks, single photon
emission computed tomography (SPECT) scan was taken to eva-
luate brain blood flow. In both groups, severity of depression
decreased. In the venlafaxine group, activity was detected in the
right posterior temporal and right basal ganglia; and in the IPT
group activity was detected in the right posterior cingulate and
right basal ganglia. Increase in limbic blood flow was detected
in the IPT group, and increase in basal ganglion blood flow was
detected in both treatment groups (Martin et al., 2001).
Although there are lower number of studies in this field, the
findings support that IPT ensure recovery of the metabolism
and blood flow in the prefrontal cortex, cingulate cortex and
basal ganglia. More research is needed in this field.
Psychodynamic Therapies and Neurobiology
Psychodynamic psychotherapy model is based on the idea
that depression is related to unconscious conflicts and desires.
According to this, interpersonal relationships are closely related
to developmental characteristics brought from childhood and
these characteristics are seen as transference in therapeutic
relationship. Psychodynamic therapy focuses on how present
losses and stressors revive past losses and traumas (Gabbard &
Bennett, 2009). Although there are many opinions and theories
in this field, these will not be discussed here. Psychodynamic
psychotherapy can be applied short or long term. Long-term
psychodynamic psychotherapy aims to provide an insight and
reevaluation of experiences related to the depressive pathology.
In the first and one study in this field, changes caused by
psychodynamic psychotherapy on left anterior hippocampus,
amygdala, subgenual cingulate and medial prefrontal cortex
regions are investigated using fMRI in MDD (Table 3). De-
pression patients were applied psychodynamic therapy for 15
months and activation values obtained before the therapy was
compared with those obtained after the therapy. After psycho-
therapy, it was found that depressive symptoms decreased,
accompanied by a decline of activity in the cingulate and me-
dial prefrontal cortex, which was high before the therapy
(Buchheim et al., 2012). Findings obtained through psycho-
dynamic psychotherapy show that abnormal activities in the
prefrontal cortex and cingulate cortex in the depression are
regulated, which supports results of the CBT and IPT.
In major depressive disorder, emotional information proc-
essing mechanisms are disrupted in relation to the functional
anomalies in the prefrontal corex, anterior cingulate cortex, t
Copyright © 2012 SciRes.
G. SÖZERI-VARMA, F. KARADAĞ
Copyright © 2012 SciRes. 861
The studies of interpersonal psychotherapy.
Study Subjects, the rapy, duration of therap yImaging Results
IPT, n: 14
paroksetine-treatment, n: 10
healthy control, n: 16
Before treatme nt, in MDD
Prefrontal kortex, caudate, thalamus
Decrease d metabolism
After treatment, in MDD
Decrease d metabolism
Right prefrontal cortex, left cingulate gyrus
Bilateral prefrontal cortex, left cingulate gyrus
Left temporal lobe
MDD, n: 39
IPT or paroksetine-treatment,
Different depressive symtoms improvement associated with
Decrease d metabolism
Ventral frontal lobe ventral anterior cingulate gyrus
anterior insula activity
dorsal anterior cingulate dorsolateral prefrontal cortex
IPT, n: 13
venlafaksine-treatment, n: 15
activity, right posterior cingulate, basal ganglia increase
limbic blood flow and basal ganglion
Activity, right posterior temporal, basal ganglia increase
Basal ganglion blood flow
Note: IPT: Interpersonal psychotherapy, PET: Positron emission tomography, SPECT: single photon emission computed tomography.
The studies of psychodynamic psychotherapy.
Study Subjects, the rapy, duration of therap y Imaging Results
long-term psychodynamic psychotherapy, n: 16
healthy control, n: 17
Before treatme nt, in MDD
Hippocampus, amygdala subgenual cingulate medial
The same areas
Note: fMRI: Functional magnetic resonance imaging.
amygdala and other limbic system structures. In general, it is
understood that the controlling effect of the prefrontal cortex on
the cingulate cortex and amygdala decreases and that the func-
tional relationship between these structures is disrupted. How-
ever, it is possible to interpret some of the functional changes in
neural cycles as a result of the compensatory mechanisms. The
determination of the functional changes caused by psycho-
therapies in brain structures related with emotional processes is
very exciting. Even though the number of studies in this field is
increasing, it is still fairly low. The studies that have been car-
ried out show that these three psychotherapy methods (cogni-
tive behavioral psychotherapy, interpersonal psychotherapy,
psychodynamic psychotherapy) are effective in the treatment of
depression and that they provide a similar level of amelioration
in depressive symptoms with antidepressants. The theoretical
explanation of depression pathophysiology and the methods
used for treatment differ between these three psychotherapy
methods. However, it is observed that similar changes in the
brain structure arise (despite the fact that it is difficult to gener-
alize due to the small amount of data). New studies are required
examining the relationship between the symptoms that are re-
covered via the applied psychotherapy method and the changes
in the brain.
Since there is limited number of studies on neurobiological
effects of psychotherapies, the data is derived from limited
number of patients. More research should be conducted to gen-
eralize the findings. It is observed that the studies focus on
short-term effects of psychotherapies. In fact, long-term evalua-
tion of effects of psychotherapies on emotions, thoughts and
behaviors may be more enlightening. In a disorder with such
high risk of recurrence, there is need for studies aimed to inves-
tigate long-term results of psychotherapies and their effects on
It is known that both biological and psychosocial factors play
a role in emergence of depression, and both drugs and psycho-
therapy have effects through different mechanisms on patients.
Researches that investigate neurobiological effects of psycho-
G. SÖZERI-VARMA, F. KARADAĞ
therapies show that different psychotherapy methods lead to
metabolism and activity changes in the direction of recovery in
especially the cingulate cortex, prefrontal cortex and amygdala.
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