How Antidepressants Reverse the Effects of Depression in the Hippocampus: A Review

1. 1
Angela Pascuzzi
Dr. Karsten
Scientific Literature
16 December 2016
How Antidepressants Reverse the Effects of Depression in the Hippocampus
Abstract
Research shows that depression is caused by the impact of external stress and internal
changes in the hippocampus rather than an inadequate concentration of neurotransmitters in
synapses. We now know that the brain is constantly changing and reorganizing its synapses
which leads to reorganization of whole regions of the brain. Some neuroplastic changes are
harmful and can cause mood disorders such as depression. The main neurons in the brain that
depression affects are in the dentate gyrus, CA1, and CA3 region in the hippocampus. Cell death
in these regions can be caused by acute or chronic exposure to stress. The overall effect of cell
death is a decrease in volume of the hippocampus. Other protein concentrations can also add to
depressive effects. Brain-derived neurotrophic factor, or BDNF, pCREB, PSA-NCAM, and
GAP-43 in low concentrations in the hippocampus have been shown to increase depressive
effects on a patient. BDNF helps neurons grow in the hippocampus, so low concentrations due to
stress can cause cell death. PSA-NCAM is found in new neurons so low concentrations indicate
little proliferation of neurons. When neurons are not growing, antidepressant effects cannot take
place. GAP-43 helps regenerate neurons and pCREB is the first protein found in new neurons,
with PSA-NCAM concentrations increasing when new neurons mature. Decreased dendritic
spine density and a decrease in strength and frequency of synaptic impulses in the hippocampus
also increase the risk for depression. Due to the multitude of causes of depression, current

2. 2
antidepressants could target any one deficiency. This opportunity for antidepressants to
specifically target one or more causes of depression can increase the specificity one has in order
to treat depression. Individuals can benefit from unique methods such as polypharmacy, where
two or more antidepressants are prescribed, due to its increased specificity. Patients with
depression have decreased volume of the hippocampus, specific protein concentrations, dendritic
spine densities, synaptic impulse speeds, and changes in behavior. With these definitive causes
of depression, antidepressants can be designed to specifically target one of these causes.
Introduction
It was previously thought that depression was caused by a low concentration of
neurotransmitters in neuronal synapses. More research has found that depression is caused by
external stress that affects the whole hippocampal area of the brain, specifically the dentate gyrus
and the cornu ammonis, or Ammon’s horn (Duman 2002). The hippocampus is in the middle of
the temporal lobe in the brain and its shape resembles a seahorse. It is known for controlling long
term memory and regulating emotions (Martini et al. 2014). Two structures known as Ammon’s
horn and the dentate gyrus make up the middle of the hippocampus. Ammon’s horn can be
divided into different areas referred to as CA1, CA2, CA3, and CA4 (Hayman et al. 1998). These
two areas of the hippocampus are easily measurable and are shown to be altered in patients with
depression. This also make Ammon’s horn and the dentate gyrus good targets for antidepressant
therapy. Antidepressants are quickly becoming one of the most commonly prescribed
medications with depression affecting about 350 million people worldwide (Steel et al. 2014).
How Depression Affects the Hippocampus: An Overview
Depression causes changes in mood, cognitive disturbances, and fundamental biological
drives. The numerous diverse symptoms suggest that depression affects many different areas of

3. 3
the brain; however, the most studied changes are in the hippocampus. The hippocampus contains
multiple stress and protein concentration receptors making it sensitive to minute changes
(Warner-Schmidt and Duman 2006). Depression causes a decrease in the overall volume of the
hippocampus and decreased levels of specific protein and neuronal cell concentrations (Adachi et
al. 2008). Measuring the effects depression causes in the hippocampus leads to better
mechanisms of antidepressant medications; the more scientists learn about these changes, the
more specific and efficient medications they can create. Improvements to antidepressant design
to target specific causes of depression such as decreases in specific protein concentrations,
volume of the hippocampus, synaptic impulse speed, dendritic spine density, and changes in
behavior will make treating depression more precise.
Previously, the focus of scientific research was on the external symptoms depression
causes. Now, with advanced technologies, scientists can measure internal changes in the brain as
well. Patients with depression commonly experience a decrease in neurons, glia, and dendrite
length (Duman 2002). Neurons are responsible for transmitting information between cells. Glia
are the most abundant neural cells in the central nervous system. They do not have axons or
dendrites and cannot illicit action potentials like neurons can; instead, glia are supporting cells to
neurons. Glia are divided into oligodendrocytes, microglia, and astrocytes. Oligodendrocytes add
a sheath called myelin to axons that increases the speed in which action potentials can travel
between cells. Microglia are phagocytic cells that help stimulate an immune response. Astrocytes
give neurons nutrients, maintain ion homeostasis, secrete growth factors, and help with immune
responses (Martini et al. 2014). Dendrites are the portion of a neuron where signals are
transmitted from axons. Dendrite length determines the strength of the signal being sent. The
decrease in neurons, glia, and dendrite length can come from exposure to stress.

4. 4
Short term and long term stress are known to decrease the frequency of signals sent in the
hippocampus (Rocher et al. 2004). This decrease in signal frequency is the precursor to
instrumental changes that lead to depression. Both acute and chronic exposure to stress result in a
concentration decrease in a protein called brain-derived neurotrophic factor (BDNF) throughout
the hippocampus (Adachi et al. 2008). Normally, BDNF helps regulate synaptic plasticity
mechanisms that enhance learning and memory. Synaptic plasticity is defined as an induced and
persistent variation in synaptic strength (Cunha et al. 2010). Increased synaptic strength is
important for learning and making memories. A decrease in BDNF decreases the number of
neurons stimulated, the length of these neurons, and therefore the overall volume of the
hippocampus (Adachi et al. 2008).
Regions of the Hippocampus that are Affected by Depression
The main regions in the brain that depression affects are in the dentate gyrus, CA1, and
CA3 regions in the hippocampus. The dentate gyrus receives stimuli from the entorhinal
complex, the most superficial area in the hippocampus. Neurons in the dentate gyrus then fire
signals to the CA3 region of the hippocampus and neurons in the CA1 region are then stimulated
by the CA3 neurons. A decrease in these neurons decreases the strength of the stimuli being
received by the CA1 region. The decrease in signal strength is an unfavorable form of synaptic
plasticity which leads to depression (Martini et al. 2014). Recent studies in rats have shown that
hippocampal cells are altered in response to stress. Depression was induced in rats by inflicting
maternal neglect, social stress, and drug abuse. These stressors are representative of acute and
chronic stress. Cell death was seen in the CA1 and CA3 regions of the hippocampus of the
depressed rats (Perera et al. 2011). This study confirms that only specific regions of neurons in
the hippocampus are essential to triggering depression.

5. 5
When cell death occurs, the volume of the affected region of the brain is severely
decreased. Therefore, volumetric changes in the hippocampus are a good indication of cell death.
Bremner et al. (2000) studied hippocampal volume in depressed and non-depressed patients and
found that depressed patients with reoccurring episodes had a 19% smaller left hippocampal
lobe. However, the temporal, frontal, caudate lobes, and whole brain did not have differences in
volume. Decreased volume of the left hippocampus could be caused by elevated levels of
glucocorticoids, a steroid hormone secreted during stress. The increase of glucocorticoid levels
during depressive episodes could cause hippocampal damage. Therefore, the more recurrent
episodes, the more hippocampal atrophy occurs and relapse of depression is more likely.
However, a reduction in neurotrophins could also account for the volume reduction.
Neurotrophins are proteins in the brain, such as BDNF, that regulate development and help with
learning and memory (Huang and Reichardt 2001). Duman (2002) found that depressed patients
have atrophy of the CA3 neurons which resulted in a decreased size of the hippocampus. The
varying concentrations of specific hormones and neurotrophins caused death of the CA3
neurons, which induces reduction in volume of the hippocampus. The lack of growth and
development of particular neurons in response to protein concentrations results in volume
changes in the hippocampus.
Neuroplasticity: Regeneration of Atrophied Neurons
All neuronal loss is thought to be permanent once humans finish the developmental stage
of growth. If this was true, depression would be considered a chronic condition with no cure.
However, the dentate gyrus in the hippocampus can generate new neurons after development
(Eriksson et al. 1998). The whole brain is constantly changing and reorganizing; this effect is
called neuroplasticity. Some neuroplastic changes are harmful and can cause mood disorders

6. 6
such as depression or bipolar disorder. Over time, atrophy of hippocampal neurons and
decreased density in glia occurs in depressed patients (Fuchs et al. 2004). If neuronal atrophy
was an effect of plasticity, normal brain rearrangement, rather than physical trauma, it can be
reversed. This is the target of antidepressant therapy and how patients with depression can
recover. Unlike most other areas of the brain, neuronal loss can be reversed in areas of the
hippocampus by specifically altering the synapses between neurons and the strength in their
connectivity (Martini et al. 2014). This process and ability is termed synaptic plasticity. Synaptic
plasticity in areas such as the dentate gyrus, CA1 or CA3 region of the hippocampus can lead to
neuroplasticity of the entire hippocampus.
Target of Antidepressant Therapy: Volume Changes
Antidepressants reverse effects depression has on the brain, specifically decreased
hippocampal volume, through neuroplasticity. Many animal models can mimic human
neuroplasticity, allowing scientists to extensively research this process. Czéh et al. (2001) found
that in male tree shrews, a seven day antidepressant therapy counteracted stress-induced changes
in both the volume of the hippocampus and in cell density. This increase in volume is from the
regeneration of neuron connections in the hippocampus. Malberg and Duman (2003) emphasize
this idea with their study on rats. Like Czéh et al., they also found an increase in volume after
chronic (28 day) and acute (nine day) antidepressant treatment. Their study concludes that
neuroplasticity, or regeneration of atrophied neurons, is responsible for such effect. Adachi et al.
(2008) also found that chronic antidepressant treatment increased the previously low
concentrations of BDNF in mice. The increase in BDNF concentrations also led to an increase in
hippocampus volume.
Target of Antidepressant Therapy: Protein Concentration Variations

7. 7
Concentrations of other proteins also show plastic affects in the hippocampus. Sairanen et
al. (2007) tested the plasticity of three proteins, PSA-NCAM, GAP-43, and pCREB. PSA-
NCAM and pCREB are commonly found in new neurons while GAP-43 assists in regenerating
neurons. Rats were treated acutely and chronically with an antidepressant. After 21 days, they
found that expression of all three proteins increased in the hippocampus as well as two other
regions of the brain. However, the acute treatment only increased expression of pCREB,
indicating that pCREB can cause quick and selective plastic changes. The increased
concentrations of GAP-43 and PSA-NCAM can produce more substantial changes over time in a
more widespread manner.
Target of Antidepressant Therapy: Dendritic Spines and Synaptic Impulses
Small projections of the dendrite, known as dendritic spines, are part of the neuron that
receive stimuli. Dendritic spine density changes during depression as well as volumetric and
protein concentration changes. Dendritic spine density varies in response to stress, medications,
environmental factors, and differing neurotransmitter concentrations. Norrholm and Ouimet
(2001) induced stresses which showed to greatly decrease dendritic spine density in rats. They
gave chronic antidepressant treatment and saw complete reversal of decreased density of
dendritic spines. Therefore, antidepressant therapy can help increase the density in damaged
dendritic spines in depressed patients. However, antidepressants were not initially designed to
have this effect. There are many different classes of antidepressants, the most common being
SSRIs like fluoxetine (Prozac) and SNRIs like venlafaxine (Effexor). Selective serotonin
reuptake inhibitors and serotonin norepinephrine reuptake inhibitors primary mechanism of
action is to allow more serotonin (and norepinephrine in SNRIs) to linger in the synapses of
neurons. Concentrations of neurotransmitters in synapses can alter synaptic impulse speed. When

8. 8
CA1 neurons receive high frequency stimulation (about 100 impulses/second) in the
hippocampus, long term potentiation (high frequency of impulses throughout the hippocampus)
occurs. Long term potentiation results in an increase of synaptic efficiency. The synaptic
efficiency helps dendritic spines grow, therefore reversing depressant effects. When CA1
neurons are excited by impulses at low frequency stimulation (about 1 impulse/second), long-
term depression of the synapse occurs. The same synapses that show increased efficiency when
stimulated frequently can also show depression when stimulated weakly by CA3 neurons.
Hajszan et al. (2005) observed synaptic density of female rat hippocampi in relation to
antidepressant treatment. Rats treated with fluoxetine (a SSRI) had a great increase in density of
spine synapses in CA1 by day five (acute treatment) and levels remained high by day 14 (chronic
treatment). Density in CA3 was lower than that in CA1 on day five but levels increased in CA3
by day 14. However, these levels were still lower than CA1 levels on day 14. All levels were
higher than the control group (no treatment) in which the densities did not fluctuate. The
distinction between density in CA1 and CA3 by day 5 (acute treatment) suggests that CA1
responds to antidepressant treatment effects first and CA3 receives the stimuli second. Once both
these areas are stimulated, regeneration of neurons in the dentate gyrus can occur. Therefore,
antidepressants can target both synaptic impulse speed and dendritic spine density or just one
deficiency.
Target of Antidepressant Therapy: Behavioral Changes
Another way of measuring the efficacy of antidepressants is observing behavioral effects.
Santarelli et al. (2003) observed antidepressant treated mice with and without restrictions
induced in the areas of interest within the hippocampus. After antidepressant treatment,
behavioral improvements occurred in the first set of mice but no improvement occurred in the

9. 9
mice with restrictions in the hippocampus. This implies that neurogenesis specifically in the
hippocampus is essential to antidepressant treatment and behavioral changes. An alternative
hypothesis is that antidepressants do not correct atrophy, but instead promote new ways of
coping with stress (Warner-Schmidt and Duman 2006). These new ways could include entirely
new connections. The hippocampus controls learning, memory, and mood, therefore
neurogenesis of hippocampal neurons could induce behavioral changes rather than long term
potentiation effects or regeneration of atrophied areas.
Polypharmacy: When One Antidepressant is not Enough
Older antidepressants were not originally designed to increase the hippocampal volume
by combating cell death, increase specific protein concentrations, increase the synaptic impulse
speed and dendritic spine density, and/or change behavioral effects. These changes were found
once technology allowed scientists to measure internal changes in the brain. Even with new
information on how to reverse depressive effects, it is unclear whether existing antidepressants
target some of these methods to reverse depression. It is also unclear if depression results from a
combination of all of these deficiencies or if solely one deficiency can cause depression.
Therefore, one antidepressant might not be enough to correct the neurological effects of
depression. A new treatment technique called polypharmacy uses two different types of
antidepressants. Most individual antidepressants can induce side effects among users so
combination therapy has the potential for multiple debilitating side effects. Kennedy et al. (2002)
studied the effect of an atypical antidepressant, bupropion (Wellbutrin) in combination with a
SSRI, fluoxetine (Prozac) or paroxetine (Paxil) or a SNRI, venlafaxine (Effexor) and their side
effects. Patients were either on a SSRI or a SNRI before adding bupropion. 47% of participants
reported gastrointestinal upset, 58% reported dry mouth, 37% reported increased sweating, 58%

10. 10
reported frequent headaches, and 11% had mild tremors before the addition of bupropion. After 8
weeks of combination therapy, tremor increased to 22%, reports of sweating were the same, and
gastrointestinal upset, dry mouth, and headaches had all decreased (28%, 28%, and 39%
respectively). Insomnia was newly reported in 22% of individuals and sexual desire, arousal, and
orgasm all increased after treatment with combination therapy. Thus, no insufferable side effects
have appeared in this study of polypharmacy and previous side effects decreased. Álamo et al.
(2007) had similar success in combining reboxetine (Edronax) and venlafaxine which are both
SNRIs. They found that 47.5% of their participants saw an improvement in their depression.
Therefore, polypharmacy increases the variety and specificity one could use in treating
depression. The combination of two antidepressants theoretically can help target more than one
cause of depression and therefore improve the probability of effective treatment. As scientists
discover more about depression and the brain, the more complex depression seems to be.
Therefore, we need more precise and effective treatments and polypharmacy can deliver the
specificity one needs to overcome depression.
Conclusion
Depression is becoming a very common mental illness. It is a complex disorder and
treating used to be even more obscure. Depression can decrease hippocampal volume, specific
protein concentration, synaptic impulse speed, dendritic spine density, and alters behaviors. This
variety in causes of depression allows antidepressants to target one or more deficiencies. Now
that the causes of depression are more definitive, antidepressants can be designed to specifically
target these causes. Individuals can also benefit from unique methods such as polypharmacy due
to its increased specificity (Leistedt and Linkowski 2013). A contemporary, flexible view of

11. 11
hippocampal anatomy is essential for treating mood disorders and developing medications to
target depressive effects.

12. 12
References
Adachi, M., M. Barrot, A. Autry, D. Theobald, and L. Monteggia. 2008. Selective loss of brain-
derived neurotrophic factor in the dentate gyrus attenuates antidepressant
efficacy. Biological Psychiatry 63:642-49.
Álamo, C., F. López-Muñoz, G. Rubio, P. García-García and A. Pardo. 2007. Combined
treatment with reboxetine in depressed patients with no response to venlafaxine: a 6-week
follow-up study. Acta Neuropsychiatrica 19:291–296.
Bremner, J. D., M. Narayan, E. R. Anderson, L. H. Staib, H. Miller, and D. S. Charney. 2000.
Hippocampal volume reduction in major depression. American Journal of
Psychiatry 157:115-118.
Cunha, C., R. Brambilla, and K. L. Thomas. 2010. A simple role for BDNF in learning and
memory? Frontiers in Molecular Neuroscience 3:1-14.
Czéh, B., T. Michaelis, T. Watanabe, J. Frahm, G. De Biurrun, M. Van Kampen, A.
Bartolomucci, and E. Fuchs. 2001. Stress-induced changes in cerebral metabolites,
hippocampal volume, and cell proliferation are prevented by antidepressant treatment
with tianeptine. Proceedings of the National Academy of Sciences of the United States of
America 98:12796-12801.
Duman, R. 2002. Pathophysiology of depression: the concept of synaptic plasticity. European
Psychiatry 17:306-310.
Eriksson, P., E. Perfilieva, T. Björk-Eriksson, A. Alborn, C. Nordborg, D. Peterson, and F. Gage.
1998. Neurogenesis in the adult human hippocampus. Nature Medicine 4:1313-1317.

13. 13
Fuchs, E., B. Czéh, M. Kole, T. Michaelis, and P. Lucassen. 2004. Alterations of neuroplasticity
in depression: the hippocampus and beyond. European Neuropsychopharmacology
14:S481-S490.
Hajszan, T., N. J. Maclusky, and C. Leranth. 2005. Short-term treatment with the antidepressant
fluoxetine triggers pyramidal dendritic spine synapse formation in rat
hippocampus. European Journal of Neuroscience 21:1299-1303.
Hayman, L.A., G. N. Fuller, J. E. Cavazos, M. J. Pfleger, C. A. Meyers, and E. F. Jackson. 1998.
The hippocampus: normal anatomy and pathology. American Journal of Roentgenology
171:1139-1146.
Huang, E. J., and L. F. Reichardt. 2001. Neurotrophins: roles in neuronal development and
function. Annual Review of Neuroscience 24:677–736.
Kennedy, S., S. McCann, M. Masellis, R. McIntyre, J. Raskin, G. McKay, and G. Baker. 2002.
Combining bupropion sr with venlafaxine, paroxetine, or fluoxetine: a preliminary report on
pharmacokinetic, therapeutic, and sexual dysfunction effects. Journal of Clinical Psychiatry
63:181-186.
Leistedt, S. and P. Linkowski. 2013. Brain, networks, depression, and more. European
Neuropsychopharmacology 23:55-62.
Malberg, J. and R.S. Duman. 2003. Cell proliferation in adult hippocampus is decreased by
inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28:1562-
1571.
Martini, F. H., M. Timmons, and R. B. Tallitsch. 2014. Human Anatomy, 8th
ed. Pearson
Education, Inc., CA, pp 685-693.

14. 14
Norrholm, S. and C. Ouimet. 2001. Altered dendritic spine density in animal models of
depression and in response to antidepressant treatment. Synapse 42:151-163.
Perera, T., A. Dwork, K. Keegan, L. Thirumangalakudi, C. Lipira, N. Joyce, C. Lange, J. Higley,
R. Rosoklija, H. Sackeim, and J. Coplan. 2011. Necessity of hippocampal neurogenesis for
the therapeutic action of antidepressants in adult nonhuman primates. Public Library of
Science (PLOS) One 6:1-13.
Rocher, C., M. Spedding, C. Munoz, and T. Jay. 2004. Acute stress-induced changes in
hippocampal/prefrontal circuits in rats: effects of antidepressants. Cerebral Cortex 14:224-
229.
Sairanen, M., O. F. O’Leary, J. Knuuttila, and E. Castren. 2007. Chronic antidepressant
treatment selectively increases expression of plasticity-related proteins in the hippocampus
and medial prefrontal cortex of the rat. Neuroscience 144:368-374.
Santarelli, L., M. Saxe, C. Gross, A. Surget, F. Battaglia, S. Dulawa, N. Weisstaub, J. Lee, R.
Duman, O. Arancio, C. Belzung, and R. Hen. 2003. Requirement of hippocampal
neurogenesis for the behavioral effects of antidepressants. Science 301:805-809.
Steel, Z., C. Marnane, C. Iranpour, T. Chey, J. Jackson, V. Patel, and D. Silove. 2014. The global
prevalence of common mental disorders: a systematic review and meta-analysis 1980-2013.
International Journal of Epidemiology 42:476-493.
Warner-Schmidt, J. and R. Duman. 2006. Hippocampal neurogenesis: opposing effects of stress
and antidepressant treatment. Hippocampus 16:239-249.