Biological effects of stress in depression – antidepressants vs alternative treatment
Ceyrine M. Pellikaan 10274960
10 EC September - December
MSc. In Brain and Cognitive Sciences, Cognitive Science track
Supervisor: Dr. Harm J. Krugers
MSc. Vincent Tijms
Co-Supervisor: Dr. Paul J. Lucassen
Institute for Interdisciplinary Studies
Abstract
Depression is highly prevalent in western society. Depression has a genetic contribution,
however, environmental factors such as adverse life events in childhood, negative cognitive
styles, and chronic stress also form risk factors. The biological mechanisms in depression are
complicated since they involve different highly interconnected systems. Antidepressant therapy is
currently the first choice of treatment. However, alternative therapies, such as mindfulness and
cognitive therapy, have recently been incorporated in treating depression. The aim of this review
is to compare the impact of these therapies on the biological mechanisms of depression and
examine whether the alternative treatments could substitute the use of antidepressants or rather
have a complementary function. The most important findings are that antidepressant and
alternative therapy have similar beneficial effects on the underlying biological aspects of
depression, such as the HPA-axis, BDNF and brain structures, monoamines and the immune
system. However, it is not possible to conclude that alternative therapy could substitute
antidepressant therapy. Partly, because almost half of the patients treated with either therapy were
non-responders. A better understanding of the biological mechanisms in depression and
intervention is recommended as it might resolve why patients do not respond, offer them an
alternative therapy, and optimally, increase the rate of response; it may serve to prevent MDD;
and it may aid in locating the exact problem of the disorder which consequently might lead to
1. Introduction
Major Depressive Disorder (MDD) is characterized by fatigue, depressed mood, loss of interest,
decreased concentration and lowered capacity of decision making according to the Diagnostic
and Statistical Manual of Mental Disorders (DSM IV, American Psychiatric Association, 2000).
Depression is highly prevalent in western society; in the Netherlands almost a quarter of the
women and 13.1% of the men experience at least one depressive episode in their lifetime (“Feiten en cijfers depressie,” 2010). Worldwide, more than 350 million of people suffer from depression
(“Depression,” 2012). In addition, the incidence of many diseases such as coronary diseases,
Diabetes Type II, metabolic syndrome, osteoporosis, cognitive aging and dementia, are higher in
patients with depression (Wolkowitz, 1999). The prevalence, risk for other diseases and high
recurrence rate make depression a burden to the individual and their families.
What the underlying causes of depression are, is still a matter of debate. Although various
risk factors are statistically associated to depression, the disorder cannot be attributed to one risk
factor alone (Beekman & Marwijk, 2008, p. 16). Depression is familial (Sullivan, et al., 2000)
hence the disorder has partly a genetic contribution. However, environmental factors such as
adverse life events in childhood, negative cognitive styles, and chronic stress also form risk
factors for depression which in combination with genetics, increase the vulnerability of
developing depression (Charney and Manji, 2004). Stress seems to be a key factor in the
development of depression (Bockting et al., 2006; Kessler, 1997; Kendler et al., 2001). A stressor
can activate various systems, such as brain circuits, the endocrinological system and
immunological system (De Kloet et al., 2005). When these systems cannot return to equilibrium,
impact of stress on these systems and how this can evolve in to a depression for two reasons: 1) It
serves as a roadmap to understand how treatment of MDD affects these biological mechanisms;
2) It enables a comparison of different treatments and whether one or another treatment may (or
not) reestablish homeostasis. The aim of the present review is to compare the impact and efficacy
of antidepressant treatment with alternative treatments, such as Cognitive Therapy and
Mindfulness in patients with Major Depressive Disorder, and examine whether alternative
treatment could substitute the use of antidepressants or have a complementary function.
Antidepressant treatment is currently the first choice of treatment for depression. A little over a million of the Dutch population used antidepressants in 2013 (“GIPdatabank,”2014).
There are many different antidepressants on the market, but the main types comprise Monoamine
oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), Selective Serotonin Inhibitors
(SSRIs) and atypical antidepressants which also inhibit the reuptake of serotonin in addition to
the reuptake of other neurotransmitters. Examples hereof are: serotonin norepinephrine reuptake
inhibitors (SNRIs), norepinephrine – dopamine reuptake inhibitors (NDRIs), selective
norepinephrine reuptake inhibitors (NRIs), serotonin antagonist/reuptake inhibitors (SARIs), and
others. Currently, SSRIs and atypical antidepressants, also referred to as second generation
antidepressants, are the most commonly used, since it targets specific neurotransmitters, in
contrast to TCAs, which target some neurotransmitters that cause unwanted side effects. In spite
of antidepressants being the first choice, 53% of the patients do not achieve remission and 37%
do not achieve a response (Gartlehner et al., 2011). A response is defined as at least 50% of
amelioration of baseline symptoms and remission as full improvement.
Mindfulness and Cognitive Therapy (CT) are non-pharmacological therapies commonly
ongoing stream of internal and external stimuli as they arise (Baer, 2006). According to Kabat-Zinn‟s program, the essence is to be fully in the present moment, without evaluating it, focusing
on the reality as it is, thus accepting it, without trying to change it or thinking engaging in
discursive thought (Teasdale, 1995). Mindfulness aims to help individuals to become aware of
their negative thoughts, and disrupt ruminative depressive processing (Teasdale et al., 2000). One
manner of becoming aware of the moment is to attend internal experiences such as bodily
sensations, thoughts, emotions, sights or sounds, without evaluating them (Baer, 2006). There are
various types of mindfulness therapies used for treatment of depression, with the most common
and well-studied being: Mindfulness-Based Stress Reduction (MBSR) and Mindfulness- Based
Cognitive Therapy (MBCT). MBSR is an 8-week program that involves training in mindfulness
meditation and discussion on stress and life skills and is used as a treatment for patients with inter
alia; chronic pain, fibromyalgia, multiple sclerosis, and generalized anxiety disorder and panic.
MBCT was developed specifically for patients with depression with the purpose to help them
disengage from patterns of negative thinking.
Cognitive therapy, also referred to as Cognitive Behavioral Therapy (CBT) is an approach
based on information processing. According to Beck (2005), cognition is biased because it
depends on the experience of an individual. In depression, cognition is negatively biased due to
the negative representation the individual has of him/herself and his/her personal world and
future (Beck, 1963). The negative meanings have bodily effects, e.g., arousal, activation, facial
expression, and other depressive responses in the body, which will in turn affect the sensory
input, which is also biased. This loop is reinforced, since new input will convey more negative
meanings, creating a depressive interlock (Teasdale and Barnard, 1993). Cognitive therapy aims
non-depressogenic pattern, by maintaining some of the core elements of the depressive pattern and
changing some of the elements to create new patterns (Teasdale, 1995). In other words, cognitive
therapy helps individuals to identify the negative thoughts accompanying certain experiences,
question the validity of those thoughts, and look for alternative patterns (De Rubeis, et al., 2008).
The difference between mindfulness and cognitive therapy, is that mindfulness addresses
the relationship one has with his/her thoughts, in other words, one is aware of one‟s thoughts but
is not reactive, i.e., not feeding these thoughts. CT on the other hand, addresses the content of the
thoughts, e.g., by changing negative into positive thinking (Ivanovski & Malhi, 2007). CT and
CBT are many times used interchangeably. However, CBT is an umbrella term as it also includes
behavioral therapy. In this review, MBSR and MBCT, and CT and CBT, will be addressed as
mindfulness and cognitive therapy (CT), respectively and will be jointly referred to as alternative
therapy. Data referring to the effectiveness of treatment will be reported on CT and not on
mindfulness, since the latter is not specifically used to treat MDD. However, valuable
information obtained from studies on mindfulness treatment of other disorders (which included
depressive symptoms), was incorporated in this paper.
In spite of the difference between mindfulness and CT, in this review both therapies will be proposed as “alternative treatments” to antidepressant medication. The clinical efficacy of the
above mentioned therapies in improving depressive symptoms and delaying recurrence has
already been assessed. Studies have reported a relapse rate of 29.5% for alternative treatments
(CT/CBT) vs 60% antidepressant medication during 1 year post-treatment follow-up (Beck,
2014; Gloaguen, et al., 1998). Although these results seem encouraging, little is known about
how these therapies work and whether they can reverse the biological impact of stress. Ergo, an
of treatment and prevention for recurrence. In this respect, this paper will address the impact of
stress on the biological mechanisms involved in depression; the effects of antidepressant and
alternative treatments on the HPA-axis, Brain Derived Neurotropic Factor and brain structure,
monoamines, and immune system; and a comparison of these treatments (Figure 1).
Figure 1. Stress is a key factor in MDD and impacts the HPA-axis, BDNF and brain structure, monoamines, and immune system. The effect of antidepressant and alternative therapy on these components will be compared.
2. Major Depressive Disorder
2.1. Symptoms and Brain areas involved in depression
The most important brain areas involved in depression are the amygdala, hippocampus and
prefrontal cortex (Sheline, 2003). The symptoms manifested in depression are believed to be
somatically related to these brain areas. For instance, loss of pleasure and interest can be
associated to the nucleus accumbens and to the prefrontal cortex, concentration to the prefrontal
cortex, sleep and appetite to the hypothalamus, guilt suicidality, worthlessness and mood to the
amygdala (Stahl, 2013). Memory deficits, also common in MDD, are associated to changes in the
hippocampus (Malykhin, 2010). The amygdala is the brain part that is most associated to
emotion: it mediates the autonomic expression, i.e., release of norepinephrine, increase in heart
rate, etc. and the cognitive experience of emotion (Kandel, p.988-992, 2000). Moreover, it might
be a storage center for emotional memory (Phelps & Anderson, 1997).
2.2. From stress to Depression: Stress sensitization
Stress causes activation in certain brain circuits involving the hippocampus, amygdala and
prefrontal cortex (De Kloet et al., 2005), which return to their normal state once the stressor is
removed. Repeated activation of these areas due to repeated exposure to stress can lead to stress
sensitization, i.e., the individual becoming more vulnerable for developing psychiatric disorders
such as depression (Stahl, 2013, p. 269). Different studies suggest a strong link between the
experience of stressful life events (SLEs) and the onset of MDD (Kessler, 1997; Kendler et al.,
2003; Monroe et al., 2009). Stressful life events (SLEs) can be understood as the termination of a
job or an important relationship (Slavich et al., 2011), parental divorce, physical abuse, or other
The stress sensitization hypothesis holds that less stress is required to elicit a major
depressive episode (MDE) (Barcusa & Iacono, 2007; Post, 1992) and with each successive MDE
the level of stress needed to trigger a recurrence decreases. In other words, the individual
becomes more vulnerable to recurrence as a function of prior MDEs (Morris et al., 2010).
In addition to the above neurological and behavioral findings, there are different theories
on the biological tenets of depression which might contribute to the stress sensitization
hypothesis. For instance, important biological abnormalities caused by stress could contribute to
the vulnerability to depression and/or recurrence (De Kloet et al., 2005). Some abnormalities
observed in individuals with MDD are changes in: brain structures or brain plasticity (Sheline et
al., 1998, 2003; Stahl, 2013; Herbert, 2012), interconnectivity between important brain regions
such limbic networks (De Kloet et al., 2005), hormone activity (Lok et al., 2012; Mc Ewen, 2007;
Jarcho et al., 2013), neurotransmission (Neves et al., 2008) and immune response (Kiecolt-Glaser
et al.,1996; Mc Ewen, 2003). Taken together, one might suggest that individuals become
vulnerable to depression and recurrence due a confluence of environmental, psychological and
biological factors.
3. The biological impact of stress
3.1. HPA – axisAll living beings strive towards homeostasis, or equilibrium. This equilibrium is
threatened by stressors (De Kloet et al., 2005; Mc Ewen, 2003). During a stressful event, the
HPA-axis, the Autonomic Nervous System (ANS), metabolic and immune system, work jointly
to promote adaptation to stressors (Mc Ewen, 1998, 2007): the ANS secretes Norepinephrine
cortex –the brain areas involved in learning, memory and cognitive processes. Simultaneously the
HPA-axis gets activated and the Corticotrophin Releasing Hormone (CRH) is secreted which in
turn triggers the pituitary gland to release the Adrenocorticotrophin Hormone (ACTH) resulting
in the release of glucocorticoids from the adrenal cortex (Timmermans et al., 2013).
Corticosteroid hormones enter the brain and bind to Minneralocorticoid receptors (MR) and
Glucocorticoid receptors (GR) which are found in the above mentioned brain areas. In concert
with NE, and other neuromodulators, they memory and learning processes (Timmermans et al.,
2013). However, due to individual differences and chronic stress, these systems fail to turn off
adequately which might lead to an imbalance in the body, or allostatic load (Mc Ewen, 2003). In
other words, traumatic experiences or an acute stress experience can challenge the coping ability
of an individual to stressful situations. When the coping ability fails, it leads to an overdrive of
the HPA-axis (Figure 2), i.e., overproduction of cortisol (hypercortisolemia), which is a common
condition in patients with MDD (De Kloet et al., 2005; Lok et al., 2012; Jarcho et al., 2013;
Vythilingam et al., 2004; Yuen et al., 2012). The over-activated HPA-axis may functionally
hamper the hippocampus, a brain region involved in episodic and declarative memory, by
reducing its plasticity (Kim et al., 2006). Such hippocampal damage results in deleterious effect
on learning and memory (McEwen & Sapolsky, 2005), reflected in biased memories; i.e.
memories are perceived as stressful, whereas in normal functioning, such memories would not be
perceived as threatening (Mc Ewen, 2007). This detrimental process leads to the interlock
proposed by Teasdale and Barnard (1993), in which the resulting biased perceptions reinforce
Figure 2. This figure illustrates that major life events, or traumatic experiences can challenge the coping ability of an individual to stressful situations leading to allostatic load resulting in adverse bodily effects and increased
vulnerability to depression (Mc. Ewen, 1998).
3.2. BDNF and brain structure
Other than regulating memory and learning processes through its receptors, cortisol also regulates
Brain Derived Neurotrophic Factor (BDNF), a neurotrophin that supports neural growth and
survival. BDNF is highly concentrated in the hippocampus and plays an important role in MDD
(Herbert, 2012). Animal studies evidenced that elevated corticosteroids due to chronic stress
decreased BDNF (Blugeot, et al., 2011). Deficient amounts of BDNF can lead to neural atrophy
in the hippocampus and other brain regions, such as the Prefrontal Cortex (Stahl, 2013).
BDNF is also regulated by monoamines. Normally these neurotransmitters promote the
release of BDNF, however, when the levels of monoamines are low, BDNF cannot be promoted,
Depression affects different brain structures. MRI studies have shown decreases in
hippocampal (Sheline et al., 2003) and amygdala volume (Sheline et al., 1998) in depressed and
remitted patients, in left hippocampus but not in other regions of interest and in hippocampus and
frontal lobe. These volume losses may partly be due a decrease in BDNF, although toxicity of
increased levels of glucocorticoids and CRH may also play a role. Reductions in grey matter
volume and glial density in the Prefontal cortex and hippocampus have also been found in
depressed patients (Sheline, 2003). The reduction in brain structure has been associated to
memory performance in women with a history of depression; the post-depressed patients scored
lower on verbal memory, associated to hippocampal function, although the general intellectual
performance was similar in both groups (Sheline, et al., 1999).
3.3. Monoamines
The three monoamines, Norepinephrine, serotonin and dopamine are important neurotransmitters
related to mood disorders. They regulate their own release but also each other. The monoamine
hypothesis states that depression is related to a deficiency of these neurotransmitters which might
lead to a compensatory up-regulation of their receptors (Stahl, 2013, p. 268).
The monoamine hypothesis stems from clinical observations of the use of Reserpine, an
antihypertensive medication that depleted monoamine stores causing depressive symptoms.
Oppositely, two other medicaments (iproniazid and imipramine) increased monoamine
transmission, resulting in antidepressant effects. Selective Serotonin Reuptake Inhibitors (SSRIs)
can produce immediate increase of monoamines however, results in mood improvement can be
observed only weeks later (Krishnan & Nestler, 2008). This might be due to the delayed effect in
to manifest (Stahl, 2013, p. 262). Although the depletion of monoamine stores reflected in
depressive mood and their enhancement in mood amelioration, not all studies fully support the
monoamine theory of depression. A meta-analyisis by Ruhe (2008) brought forward that induced
depletion of monoamines did not result in depressed symptoms in healthy subjects and only
slightly in subjects with familial history of MDD.
3.4. Immune system
Excessive glucocorticoid release plays a role in human inflammatory and autoimmune diseases.
Under normal circumstances, glucocorticoids suppress inflammation and enhance the movement
of immune cells to the site of infection (Mc Ewen, 2003). When levels of cortisol are enhanced,
as a result of stress, cortisol acts on GR receptors (Timmermans, et al., 2013), located in different
brain areas, but also in immune cells such as macrophages and T lymphocytes (Padget & Glaser,
2003). However, during chronic stress, adaptive changes lead to hypoactivity of glucocorticoid
receptors in immune cells and the limbic region (Leonard, 2000), and thus (human) individuals
have a weaker lymphoproliferative response resulting in a lower immune response. This is in line
with a study by Kiecolt-Glaser et al. (1996) who found that elderly caregivers for Alzheimer
disease patients, hence exposed to chronic stress, experienced a weaker immune response to
influenza virus vaccine than an age-matched control group.
4. Treatment for Major depressive disorder
There are different therapies available to treat depression. These treatments aim at improving a patient‟s medical condition, presumably through their actions mainly on the biological
antidepressant medication and alternative therapy– mindfulness and cognitive therapy– will be
presented.
4.1. Antidepressant Medication
4.1.1. Antidepressants action on HPA–axis
The HPA axis could be a potential target for antidepressants, since cortisol in many studies has
been found elevated in MDD patients. According to Barden et al. (1995), depressed patients with
disturbed HPA –axis function, experience increased mood and change in hormones after being
treated with antidepressants. To investigate whether the changes in the HPA –axis would also
exert effects on the long term, a tricyclic antidepressant (TCA) was administered to transgenic
mice with defective GR receptors. The results showed increased MR and GR concentrations in
the hippocampus and hypothalamus which were associated to a significant decrease of cortisol
after treatment. The reestablishment of these receptors in mice might have possibly enhanced the
negative corticosteroid feedback (Barden, 2004).
In order understand differences between antidepressants actions on cortisol levels,
Manthey et al (2011) carried out a cross-sectional study in which they compared cortisol
concentrations from 1526 human subjects with depression and/or anxiety disorder after treatment
with TCA, SSRI, and other antidepressants with non-treatment. They found the cortisol
awakening response (CAR) was flatter in TCA users than in users of other antidepressants.
Vythilingam et al. (2004) reported a decrease in urinary cortisol levels, but not in plasma cortisol,
after treatment with an SSRI. However, their subjects did not have hypercortisolemia. Manthey et
al. (2011) even found higher evening cortisol in SSRI users compared to non-users and lower
potent glucocorticoid that provides negative feedback to the pituitary gland resulting in
suppression of ACTH secretion. These findings are interesting since it shows that different
antidepressants have a different effect on the HPA-axis. However, the exact mechanism
antidepressants have on the HPA-axis has still not been unraveled.
4.1.2. Antidepressants action on BDNF and brain structure
Elevated cortisol levels in MDD are possibly associated to a decrease in BDNF, as discussed in section „BDNF and brain structure‟. Antidepressants have been reported to increase the BDNF in
rat hippocampus. Shimuzu and collegues (2003) found increased serum BDNF in antidepressant
treated patients and healthy controls compared to non-treated patients, and a negative correlation
between serum BDNF and depressive symptoms. In spite of these beneficial results in both
human and animal models; studies on rat models suggest that increase of BDNF in other brain
regions such as the nucleus accumbens, can on the contrary, increase depressive symptoms (Eisch
et al., 2003). This raises the question, whether antidepressants could selectively enhance BDNF
in certain areas such as the hippocampus, but not the nucleus accumbens, to obtain the desired
outcomes.
Antidepressants can exert their actions on different biological circuits affected by stress
and associated to depression. Research on antidepressants has shed some light on how these
circuits might be interconnected. The use of antidepressant medication has been found to increase
hippocampal volume (Sheline et al., 2003) and improve hippocampal functioning in humans
(Vythilingam et al., 2004). Antidepressants may also target the amygdala. An fMRI study
revealed that MDD patients had greater left amygdala response for masked emotional faces than
mentioned previously, structural changes in the amygdala in MDD might reflect changes in the
HPA-axis. In the hypothalamus and amygdalae from rat models, Aubry et al. (1999) measured
corticotrophin releasing factor (CRF) – also referred to as CRH – and CRF-R1 (CRF receptor).
After treating the rats with the TCA amitriptyline, there was a significant decrease in CRF
mRNA in the hypothalamic paraventricular nucleus and of the CRF mRNA receptor in the
hypothalamus and amygdala (but not in the PVN). The authors suggest that amirtriptyline can
exert an effect on the gene expression of CRF-R1 in the amygdala and CRF in the hypothalamus.
4.1.3. Antidepressant action on Monoamines
Antidepressants mainly exert their actions on the serotonergic system. A way of evaluating
serotonergic response is by measuring HPA and prolactin responses. The reason for this is that an
increase in 5-hydroxytryptophan, a precursor of serotonin, produces enhancement of
corticosteroids and prolactin. Meltzer et al. (1997) studied the effects of fluoxetine but also other
non SSRI medications on 5-HTP induced cortisol and prolactin in patients with MDD and
observed that cortisol and prolactin responses to 5-HTP were greater in patients treated with
fluoxetine (SSRI) than with TCA and in non-medicated patients. The cortisol and prolactin
concentrations between TCA and non-medicated patients did not vary significantly. These
findings suggests fluoxetine but not TCAs, stimulates serotonergic activity.
Dopamine and norepinephrine are also targets of antidepressants. One medication that
addresses both monoamines is bupropion. It has an activating and stimulating effect and is best
indicated when symptoms such as reduced positive affect, e.g.; depressed mood; loss of joy,
immediate increase of monoamines however, results in mood improvement can be observed only
weeks later (Krishnan & Nestler, 2008) as pointed out previously.
4.1.4. Antidepressant action on the immune system
Potent activators of the HPA-axis are, inter alia, pro-inflammatory cytokines. Treatment with
antidepressants can modify the alterations in noradrenergic and serotonergic neurotransmission
caused by pro-inflammatory cytokines in human studies (Leonard, 2000). Research in ex-vivo
human lymphocytes revealed a decrease in pro-inflammatory cytokines and increase in
anti-inflammatory cytokines after supplementation with antidepressants (Xia et al., 1996). These
results suggest antidepressants have an anti-inflammatory effect and that a decrease in
pro-inflammatory cytokines could attenuate the HPA-axis.
4.2. Alternative therapies: Mindfulness and CT
4.2.1. Alternative therapy action on HPA–axis
Although the HPA axis has been studied widely in depression, findings confined to
therapy are inconsistent; although most studies found in the existing literature show increased
cortisol levels after therapy, some do not. For instance, Carlson et al. (2004) showed evening
salivary cortisol of patients with breast and prostate cancer treated with MBSR was reduced and
correlated with improvement of quality of life. Tafet et al. (2005) found decreased afternoon
plasma cortisol levels in patients with GAD after CT compared to non-treated patients. The
decrease in cortisol levels was positively correlated with the decrease in depressive symptoms.
Lok et al. (2012) observed CT had a borderline significant effect of steeper cortisol declines over
the day during 2 year follow-up, whereas baseline levels of cortisol were not different between
that received Treatment as Usual (TAU) and CT compared to TAU only. Matousek et al. (2011)
on the other extend, found a prolonged increase of cortisol after awakening in patients treated for
breast cancer who received MBSR.
Cortisol concentrations in MDD patients can, according to Boctking et al. (2006), predict
the effectiveness of therapy. They compared two groups of patients; one treated with TAU and
the other with TAU and CT. They observed CT was helpful to prevent relapse, and found
significant treatment interactions with morning cortisol levels. In patients that had received TAU,
low levels of cortisol predicted earlier recurrence. In patients that had received CT, cortisol levels
did not influence recurrence, but there was as trend that higher cortisol levels predicted earlier
recurrence. There was however a difference in number of previous episodes between both groups,
which might have influenced the outcomes. The CT group had median of four previous episodes
and TAU a median of three. As reported by Lok et al. (2012), patients that experienced ≥5
previous episodes had in average lower cortisol concentrations than people that had <5. This
might be the reason that the patients in the CT group had lower cortisol levels and therefore
benefitted more from CT. Moreover, patients with a high number of MDEs benefitted less from
TAU.
Individual differences in mindfulness, that is, the capacity of an individual of being in a
state of moment awareness – measured with the 15-item Mindful Attention Awareness Scale
(MAAS) – are also important since according to Brown et al. (2012) they moderate
neuroendocrine responses. Brown and colleagues assessed mindfulness and found that cortisol
responses to a social evaluative threat task was moderated by mindfulness, i.e., cortisol responses
4.2.2. Alternative therapy action on BDNF and brain structure
As mentioned previously, stressful experiences are associated to the down-regulation of BDNF.
Perroud et al. (2013) studied how therapy could affect BDNF in subjects with borderline
personality disorder. The subject underwent four weeks of intensive dialectical behavior therapy
(DBT). This therapy is designed for Borderline personality disorder, incorporates mindfulness
and has a dialectic approach on the world, i.e., it views reality as two opposing effects that
synthesize to form a new reality with also opposing forces and continuous changes. The focus is
thus on acceptance and change. To assess changes in BDNF they measured methylation at BDNF
CpG exons I and IV as plasma BDNF protein levels in patients and healthy controls. After
therapy levels were measured again and they found BDNF methylation had increased and
negatively associated with depression scores. However, patients‟ BDNF levels were already
increased before treatment compared to controls probably because all patients were on
continuous antidepressant use. Although the BDNF levels increased after therapy it is still
unusual to have high baseline levels of BDNF since levels are usually reported to be rather low in
depressed patients. The use of antidepressants may thus have biased the results.
Mindfulness and CT seem to have a positive effect on brain areas that have a decreased
functionality in depression. As discussed previously, the amygdala of patients dealing with
depression is reduced in volume, albeit more active when triggered with emotional cues,
compared to controls. Golding & Cross (2010) found that their subjects, diagnosed with social
anxiety disorder showed reduced amygdala activity and increased activity in brain areas related to
attentional deployment after completion of MBSR. Moreover they improved in anxiety and
An Anatomical magnetic resonance (MR) study in healthy un-medicated subjects showed
increases in grey matter concentrations in the left hippocampus, posterior cingulate cortex and the
cerebellum after treatment with MBSR when compared to untreated subjects. These areas are
involved in learning, memory, emotion regulation, self-reference and perspective.
Other brain areas are also shown to be benefitted from alternative therapies in terms of
their connectivity. Auditory and visual network connectivity, for example, seems to be enhanced
after MBSR. An fMRI study by Kilpatrick et al. (2011) showed that subjects treated with eight
weeks of MBSR had significantly increased activity of the right dorsomedial prefrontal cortex
(dmPFC) and left medial parietal operculum; two regions of the auditory network. Visual
regions, e.g., retrosplenial cortex and the right supragenual anterior cingulate (sACC), had
increased and decreased activity, respectively. The latter was negatively correlated with the
auditory activity in MBSR (for details on these areas see reference). The decreased functional
activity of the sACC could imply, according to Kilpatrick and co. that both auditory and visual
systems are more well-defined and don‟t cross over, perhaps this could be interpreted as
“differentiation of areas”, associated to improved and more stable performance of cognitive tasks
and perceptual learning. The fact that the dmPFC was more active after MBSR is important since
this is one of the affected areas in depression. Cognitive therapy also increases prefrontal
dorsolateral activity and is associated to improved executive function (De Rubeis et al., 2008),
This can be assessed by a task involving the addition of digits with increasing speed in which the
items are presented. When the participants get something wrong, they are requested to resume the
4.2.3. Alternative therapy action on Monoamines
The effect of therapy on monoamines is not clear. Breakdown products of serotonin in urine have
been shown to be significally increased after meditation which suggests an overall increase of
serotonin during meditation (Edwards et al., 2012). However, it is still not known if mindfulness
can directly increase serotonin levels or if it does so through indirect stimulation of another brain
region (Young, 2011), as for instance the hypothalamus which induces changes in serotonergic
activity (Edwards et al., 2012). The effect of mindfulness on monoamines has been studied
through observations with PET and fMRI techniques. The findings show increased signals in
brain regions involved in regulation and attentional control which are related to an increased
release of dopamine (Young, 2011). Changes in levels of monoamines after therapy have thus not
been studied directly, but rather through the signaling in different brain regions.
4.2.4. Alternative therapy action on the immune system
Mindfulness has been shown to have an impact on the immune system. A study by Davidson et
al. (2003) showed significant increases in antibody titers in reaction to influenza vaccine in
subjects that had undergone eight weeks of MBSR compared to untreated subjects. Moreover,
with EEG they observed activation of certain left side anterior regions in the brain, which is
associated with positive emotion and an enhanced immune function (Kang et al., 1991; Davidson
et al., 1999). Davidson and colleagues observed that the magnitude of the activation of the left
sided anterior predicted the magnitude of the rise of the antibody titer as response to the vaccine.
This study was however performed on healthy subjects, and not on depressed patients. The levels
of stress the subjects experienced before and after treatment was not assessed (instead positive
it is not possible to consider whether the enhanced immune function was related to changes in
e.g., glucocorticoids. A study by Witek-Janusek et al. (2008) also showed beneficial effects of
MBSR on the immune system. Patients with breast cancer treated with MBSR showed
re-established natural killer cell activity (NKCA) and cytokine production compared to patients that
did not received MBSR.
4.3. Comparison of treatments
Comparing treatments as different as antidepressant medication to alternative treatments such as
mindfulness or Cognitive therapy is an elaborate pursuit. It is however not impossible once we
understand the effect these therapies have on the human biological mechanisms. Although such
effects need to be studied more in depth, the overview presented next on the most prominent
similarities and differences between the therapies described throughout this paper, will provide
some insight (see table 1 for a summary).
The actions of the different treatments on the HPA-axis are somewhat unclear.
Antidepressants are able to lower cortisol concentrations but not all kinds of antidepressants,
since SSRIs can also increase cortisol levels. Studies on alternative therapies also show
inconsistent effects on the HPA axis. A plausible reason might be that an altered HPA-axis is a
trait of MDD and not a state effect. From this perspective it could be possible that the HPA-axis
is less affected by therapy. Moreover, patients with many previous major depressive episodes
could have an exhausted HPA-axis and therefore lower levels of cortisol (Lok et al., 2012), hence
intra-individual differences in intrinsic cortisol levels may also account for the differences in the
Table 1
Biological impact of stress in MDD, antidepressant medication and alternative treatments
Biological component Biological impact of stress in MDD Antidepressant medication Alternative treatments HPA-axis cortisol vulnerability MDD plasticity and functionality of hippocampus
memory
mood and hormone changes
MR and GR concentrations in rodent hippocampus and hypothalamus
in cortisol
cortisol (not all studies) Levels of cortisol and previous MDEs predict outcome of therapy Level of mindfulness can moderate neuroendocrine responses
BDNF and brain structure
BDNF leading to neural atrophy in hippocampus and PFC.
hippocampal vol. amygdala vol. grey matter vol. glial density
hippocampal BDNF depressive symptoms hippocampal volume and functioning amygdala response to emocional cues CRF mRNA in rodent hypothalamic PVN CRF mRNA receptor in rodent hypothalamus and amygdala
BDNF methylation depressive symptoms amygdala activity
activity in brain areas related to attention
anxiety and depression symptoms
grey matter concentrations auditory and visual networks DLPFC associated to improved executive function
Monoamines monoamines in MDD
according to the monoamine hypothesis
serotonin leading to increase in cortisol. NE and Da
depressive symptoms observed weeks later.
breakdown of serotonin products.
signaling in brain regions involved in attentional control related to increase in
dopamine
Immune system glucocorticoids lead to
hypoactivity of GR in immune cells and limbic region resulting in a lower immune response.
modify altered NE and SE neurotransmition caused by pro-inflammatory cytokines. anti-inflammatory effect which can possibly attenuate the HPA-axis
antibody titers and
reestablished natural killer cell activity and cytokine
production
Note: Summary of the biological impact of stress on biological components affected in MDD, and the effects of antidepressant medication and alternative treatment on these components. For references see corresponding section.
Both antidepressant medication and alternative therapy seem to increase BDNF levels, a
plausible reason for the amelioration of depressive symptoms after treatment. However, not much
research has been done in human subjects and no research has been documented on the effects of
alternative therapy on BDNF in major depressive disorder per sé but in subjects with other
disorders such as borderline personality disorder (Perroud et al., 2013) who also manifest
depressive symptoms.
Both therapies have an impact on different brain structures, from which the amygdala
seems to be the most affected. This is not surprising, as the amygdala is the brain region that has
the most crucial role in depression probably as a consequence of prolonged stress. A reduction in
amygdala response was achieved with both therapies, however, the exact mechanism of action is
not evident from these studies. Possibly antidepressant actions target limbic regions directly
through monoamine increases, whereas alternative therapy targets these regions indirectly
through inhibitory actions of prefrontal/executive regions. In fact, the purpose of mindfulness and
cognitive therapy is to direct attention and regulate emotional responses, which are executive
functions (De Rubeis, et al., 2008) and thus take place in the PFC. This might explain the
findings such as increased dmPFC activity in subjects treated with MBSR and improved
performance on cognitive tasks and perceptual learning which goes alongside with the effect both
therapies exert on the hippocampus, structurally as well as functionally, paired with improvement
in memory. However, the mechanisms of action differ, since antidepressants seem to, inter alia,
target a biological cascade in some brain regions involving gene expression, resulting in e.g.,
reduced hippocampal and amygdala CRF and CRF-R1 levels. Such findings come from studies in
research, which makes such specific fields of research inaccessible. Therefore antidepressant
studies have a larger scope than research on alternative therapies.
It has been well documented that antidepressants target monoamines. This is however not
that clear in alternative therapy. Concentrations of dopamine can be investigated with fMRI, by
activation of certain brain circuits in which a particular monoamine is highly involved during a
particular task. However, PET scans are more commonly used to measure levels of serotonin and
dopamine in the brain. As mentioned previously, cortisol levels were found enhanced after
treatment with SSRIs. This effect on cortisol could have possibly been mediated by an
enhancement on serotonin. In which case, the effect of either antidepressant or alternative therapy
could be measured by the levels of cortisol which can be easily obtained through saliva or blood
samples.
It is known that patients suffering from chronic depression are more vulnerable to illness
and have a weaker immune response. The immunological responses improve after receiving
either antidepressant medication or alternative therapy. However, the methods used in the
existing literature are very different, e.g., studies on antidepressant use focused on
pro-inflammatory cytokines whereas the study on alternative therapy researched antibody titers
response.
Even though the above comparison provides some insight on the biological effects of
antidepressants treatment and alternative therapy, it does still not clarify, which therapy has a
better outcome on the long run. Therefore, in addition to the biological aspects, some practical
First of all, the duration of Antidepressants and alternative therapy can grossly range
between 4-16 weeks with some exceptions. In the majority of the studies 8 weeks of therapy is
the standard for measuring responses for scientific purposes, however 16 weeks has shown
improved results in depressive symptoms. Recommended use of ADM is nonetheless of 6 months
to achieve remission (De Rubeis et al., 2008). De Rubeis and colleagues (2005) showed
randomly assigned patients suffering from current depression had responses of 43% when treated
with CT, 50% with Antidepressant pharmacotherapy and 25% with placebo pill after 8 weeks of
therapy. These responses increased after 16 weeks to 58% for both CT and antidepressant
treatment. In other words, CT is as efficient as antidepressant medication according to this study.
Interestingly, intra-individual variety seemed to be an important factor in the therapy used;
patients with Axis I comorbidity, i.e., clinical disorders, benefited more from ADM than patients
without Axis I comorbidity. This could however be caused by the medicament paroxetine, which
has anxiolytic effects. Patients with Axis I comorbidity also benefited from CT and no difference
from patients without Axis I comorbidity was reported. Patients with the melancholic subtype of
MDD benefitted better from CT than patients that were comorbid for social phobia. A follow-up
study on those who responded to therapy (Hollon et al., 2005), revealed patients that had received
16 weeks of CT with three additional CT sessions throughout the follow-up period of 12 months,
were less likely to relapse than patients that had received 16 weeks of ADM and were off
medication, and equally likely to relapse as patients that continued receiving ADM. Continuous
follow-up during an extra following year, indicated that patients with CT had a lower recurrence
rate than patients with antidepressant treatment. This is an important finding, since it means that
CT might have a more enduring effect than ADM. Segal et al. (2010) compared the effects of
and placebo in remitted patients during an 18 month follow-up study. For those patients that were
stable remitters, i.e., their depressive symptoms did not return during remission, there was no
group difference in survival (time till recurrence). However, amongst the unstable remitters, those
who received maintenance ADM and Mindfulness therapy showed a 73% decrease in time till
recurrence compared to the patients that received placebo.
Although these findings are encouraging, only half or less of all patients with depression
responded to treatment. This still leaves an open question, namely; why? This question remains
unanswered with the research done to this day.
5. Discussion
The most important finding from this review is that both antidepressants and alternative therapy
have a beneficial impact on the underlying biological aspects of depression.
Alternative therapies such as mindfulness and cognitive therapy can indeed be a good
alternative to antidepressant medication, from a clinical point of view. As previously mentioned,
CT/CBT has resulted in a lower relapse rate compared to antidepressant medication (Beck, 2014;
Gloaguen et al.,1998). A possible reason is that the focus of therapy relies in coping and
adjusting cognitive styles. As the name implies, Mindfulness Based Stress Reduction therapy is
aimed at, inter alia, stress reduction. Taken that stress is one of the underlying causes of
depression, it is not surprising that such therapies have long lasting effects.
The comparison of therapies made in present paper, has led to new insights on the effect
of therapy on biological mechanisms affected during depression. For instance, both
therapies reduce cortisol levels, although also an increase in cortisol has been found after SSRI
therapy (Manthey et al., 2011) and after MBSR in patients with breast cancer (Matousek et al.,
2011). This discrepancy might be due to differences in group characteristics. The groups that
were treated with alternative therapy throughout the different studies were composed of patients
with breast/prostate cancer (Matousek et al., 2011; Carlson et al., 2004), patients with General
Anxiety Disorder (Tafet et al., 2005) and patients with MDD (Lok et al., 2012) who might have
different HPA-axis activity. The reason this paper includes studies on subjects that suffered from
illnesses other than MDD is on the one hand because there has not been done much research yet
on the HPA-axis in patients with MDD treated with alternative therapy, and on the other hand,
because GAD and cancer have in common a high degree of emotional distress and high cortisol
levels which are important factors in MDD. It is noteworthy to elucidate that the HPA-axis
activity can predict treatment outcome in MDD (Bockting et al., 2006). In other words, treatment
might not only regulate the HPA-axis, but the pre-treatment levels of cortisol can be indicative of
which treatment (antidepressant or alternative) will be more beneficial to the patient, reflected in
a lower level of recurrence. Nevertheless, individual differences in mindfulness (Brown et al.,
2012), coping ability (Bockting et al., 2006) and treatment-resistance (to medication) influence
treatment outcome. More research in this field is thus necessary so that therapists can take into
account individual differences when determining treatment. Moreover, the impact both
antidepressant medication and alternative therapy have on the HPA-axis should be studied
rigorously, due to the implications a disturbed HPA-axis has on health, e.g., heart and vascular
diseases, diabetes, immune system.
As mentioned previously, cortisol also regulates BDNF which is highly concentrated in
Antidepressant and alternative therapies increase BDNF, but the exact mechanism of action is
unknown. A possible reason is that (either) therapy reduces cortisol levels, although, as discussed
previously, not all studies reported decreases in cortisol. Since much research on antidepressant
therapy comes from animal studies and alternative therapy from research on other disorders than
MDD, it is difficult to compare the effect of therapies on BDNF in MDD. It is thus not possible
to conclude which therapy provides better results. Size reductions in amygdala and hippocampus,
due increased cortisol levels and decreased BDNF (Sheline et al., 1998) resulting from chronic
stress, seem to be reversed by antidepressant and alternative therapy, possibly because therapy
enhances BDNF. The study by Perroud et al. (2013) on BDNF in patients with borderline
personality disorder reported positive effects on the amygdala and hippocampus after alternative
therapy, however the patients were taking medication. Hence, the changes in amygdala and
hippocampal volume post-treatment cannot be attributed to alternative therapy alone. A research
on non-medicated subjects would shed more light on the effectiveness of alternative therapy on
BDNF.
In the existing literature there is more known about antidepressants targeting monoamines
than about alternative therapy. That is because antidepressants can be tested on animals, whereas
alternative therapy cannot. Moreover, a problem with studying the level of monoamines in the
human brain is that the levels cannot be measured directly, as in animals through microdialysis,
but need to be observed through imagery, such as PET scans. The changes observed in
monoamines after alternative therapy might be mediated by an indirect mechanism, as for
example, stress reduction. Since stress is the key factor in MDD, and a cause of the disregulation
of the HPA-axis – and biological effects on monoamines, immune system and BDNF derived
homeostasis would resurge. Normalization of the HPA-axis might thus, in theory, reestablish
monoamines. Nonetheless, regardless of the mechanisms of action, both therapies seem to exert a
positive effect by enhancing the monoamines resulting in mood improvement.
Both antidepressant medication and alternative therapy have a positive impact on the
immune system. Also here the HPA-axis plays an important role, as it modulates the immune
response but at the same time, is also activated by the immune system. Again the mechanisms of
action are not fully understood, as the studies across the literature focus on different components
of the immune system. To accurately compare the effect of antidepressant therapy with
alternative therapy on the immune system in patients with depression, it is necessary to include
more studies with patients diagnosed with MDD (rather than an illness in which depressive
symptoms is part of a spectrum of symptoms), and to use the same parameters for observation.
Although nowadays antidepressant use is still the first choice of therapy, there are some
concerns that should not be neglected and might promote a shift from antidepressant medication
to alternative therapies. One of such concerns is the side effects. TCAs for example aside from
increasing NE and Serotonin, also block muscarinic cholinergic receptors which may cause dry
mouth, blurred vision, urinary retention, constipation; and histaminic receptors that can cause
sedation and weight gain. Blockade of alpha adrenergic receptors can lead to hypotension,
dizziness; blockade of voltage sensitive sodium channels can cause coma and seizures, cardiac
arrhythmias, and cardiac arrest. MAO inhibitors also provoke an elevation of monoamines but it
can be dangerous if combined with a diet in high levels of tyramine, such as aged cheese, since it
may provoke a hypertensive crisis. Also nasal decongestants combined with MAOIs can be
dangerous (Stahl, 2013). SSRIs may cause nausea, agitation, dizziness, reduced sexual desire,
half of the patients treated with antidepressant medication do not achieve response for which a
switch of medication or an augmenting antidepressant is used. These changes in medication may
cause loss of hope in a patient resulting in demotivation (Huyser et al., 2008).
There is also a downside on alternative therapy. On the one hand, individual differences
play a major role in the effectiveness of therapy. On the other hand, there is a large variety of
alternative therapies, and whereas some therapies focus on breathing techniques, other focus on
thoughts or behavior. Whether other therapies could achieve better results, is unknown as
response percentages are mainly reported for CT/CBT. Moreover, there is still not enough
evidence on how these therapies act on the neural mechanisms involved in depression and
whether different therapies target a different mechanism. For this reason it is very difficult to
compare alternative therapy to antidepressant therapy in terms of their biological actions.
There were also some limitations to the present review. Firstly, within the alternative
therapies, only a search on Cognitive therapy and mindfulness was done. However, there are
many other alternative therapies such as vipassana, yoga, imagery, tai chi, etc. that may also
attribute valuable information to the subject in question. Secondly, not many studies using
alternative therapy were found on depression per se. Much research has been done on other
disorders, such as GAD, drug abuse, personality disorder, cancer, fibromyalgia, in which
alternative therapy resulted effective. However, all the disorders addresses in this paper included
depressive symptoms and/or chronic stress. Thirdly, only a few studies on actions of alternative
therapy on biological mechanisms were found. Other difficulties were the lack of control groups
in many studies; combined antidepressant and alternative therapy; and difference of severity of
depressive symptoms between groups within the same study. Such differences could influence
larger documentation is available for the action of antidepressants than for alternative therapy,
many studies on antidepressants are based on animal models. These studies give insight in certain
processes, however, the effects are not comparable to studies in human subjects when it comes to
e.g., measuring improvement of depressive symptoms.
Overall, the information presented in this paper shows that alternative therapy presents
promising outcomes: CT has shown to have enduring effects that extend beyond the end of
treatment, resulting in reduced risk of relapse comparable to keeping patients on medication
(Hollon et al., 2005). Moreover, alternative therapy can be helpful in the treatment of several
disorders other than depression, such as GAD and borderline personality disorder but it can also
have other applications not discussed in this paper. For instance, MBSR is able to reduce stress
levels and ruminative thinking in healthy people (Chiesa & Serretti, 2008); reduce psychological
distress, improve anxiety symptoms and fatigue in medical students (Rosenzweig, et al., 2009)
and improve visuo-spatial processing, working memory and executive functioning of students
(Zeidan, et al., 2010). In other words, mindfulness therapy is able to tackle stress, improve
cognitive performance, and decrease anxiety and fatigue; all common symptoms in depression.
Alternative therapy can thus be used for depressed patients, patients in remission to prevent
relapse/recurrence (Bockting et al., 2006), and healthy individuals. Taking this one step further;
implementation of mindfulness-based approaches before the onset of depression, for example at
schools and healthcare centers, could possibly present a reliable way of preventing depression,
since it helps reducing stress impeding it to become chronic. Such approaches could help
6. Conclusions
The initial purpose of this paper was to investigate throughout the existing literature whether
alternative therapy could reverse the biological effects of stress that lead to depression and if
affirmative, whether it could substitute antidepressant medication.
Although alternative therapy (CT/CBT) is clinically as efficient as antidepressant
medication and might even have a longer lasting effect, it is premature to conclude that
alternative therapy could reverse the biological effects of chronic stress in MDD. However,
alternative therapy does have a positive impact on the key biological systems affected in
depression. More research is needed on alternative therapy with a more homogenized
experimental setting but also with focus on the biological cascades of depression, since these are
not black and white. It is rather a complex system with many interactions and feedback loops,
such as, for example: the depressive interlock proposed by Teasdale & Banard (1993), the role of
the HPA-axis in regulating and being regulated by monoamines, and the interaction between the
HPA-axis and the immune system. These systems are sensitive to internal and external stimuli of
such large variety and different kind that it is a challenge for scientific research to map this out. A
better understanding of the biological mechanisms in depression and the effect of therapy is
recommended as it might shed light on e.g., why almost half of the patients treated with ADM or
alternative therapy do not respond to treatment. It may also aid in prevention of MDD by, for
example, regulating cortisol levels which in turn can impact BDNF, monoamines, and the
immune system. It may eventually contribute to a personalized therapy, in which the exact
problem of the disorder is located and treated. The current review provides a preliminary
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