Elainna Simpson 1

Anhedonia
Introduction
Depression is the most prevalent mood disorder and in 2017 about 7.1% of U.S. adults had at
least one major depressive disorder in their life (NIHM, 2019). Depression symptomology includes
unhappy mood, reduced energy, and changes in appetite or sleep patterns. Anhedonia, the reduced
ability to experience pleasure, is also a central symptom of major depressive disorder (MDD) (Gorwood,
2008). Anhedonia is closely connected to rewards that are needed to produce behaviors, increase the
frequency and intensity of those behaviors, and maintain behaviors (Gorwood, 2008). Assessing
someone’s reward circuitry can help to explain the lack of reward people with anhedonia receive for
performing pleasurable behaviors, therefore effecting their motivation to continue these behaviors.
Research in anhedonia is beneficial because of its prevalence, in not only MDD but also other
psychiatric disorders like schizophrenia. It can be hard for patients attempting to improve their mental
health when they do not find pleasure in the things they once did. A better understanding of symptoms
like anhedonia is important to improve the diagnosis and treatment of those who have anhedonia.
Neurobiology
Anhedonia has been associated with several structures in the brain but has been specifically
associated with a deficit of activity in the ventral striatum (including the nucleus accumbens) and an
excess of activity in the ventral region of the prefrontal cortex (including the orbitofrontal cortex) (Figure
1 & 2) (Gorwood, 2008; Schlaepfer et al., 2008). Less activity in the ventral striatum is associated with
less interest and pleasure in activities (Keller et al., 2013). The nucleus accumbens is implicated in
anhedonia due to its role in anticipation of reward but also because it receives projections from emotion
regions (amygdala, orbitofrontal cortex), motor regions (dorsal caudate and globus pallidus), and
memory regions (hippocampus) (Figure 1). The nucleus accumbens also projects to areas where
emotions are processed (Gorwood, 2008). These structures’ function and circuitry demonstrate the
physical behaviors of anhedonia which connects the emotion and memory of a past activity’s level of
pleasure and the motor movement to act on that activity. Gorwood (2008) also implicates a ventral
system (amygdala, insula, ventral striatum, and ventral regions of the prefrontal cortex and anterior
cingulate gyrus) in anhedonia due to its importance in identifying emotional significance, producing an
affective state, and regulating an autonomic response for that state (Figure 1 & 2). The orbitofrontal
cortex links reward and hedonic experience due to its role in learning and decision-making (Figure 1 &
2). Since anhedonia is a complex behavior, the connections between these structures are all involved in
having a pleasurable response or lack thereof.
Dopamine (DA) is the central neurotransmitter within the reward system since it is released
from the nucleus accumbens and allows for approach responses and motivation. For anhedonia, there is
a reduction in dopamine firing, but there is a distinction in where that reduction occurs, for decreased
feelings of rewards there is a decrease of DA firing in the nucleus accumbens shell, but the abnormal
ability to distinguish the anticipated pleasure of a naturally desirable stimulus is due to a decrease in DA
firing in the medial prefrontal cortex and the nucleus accumbens core (Gorwood, 2008). Opioid
receptors also mediate reward and opioid antagonists block the stimulation of DA release on the
nucleus accumbens shell, usually in motivating activities such as doing drugs, eating, or having sex.
Serotonin modulates both dopamine and opioid release in the reward pathway. The use of SSRIs raise
the threshold and reduces the firing rate of DA neurons in the ventral tegmentum area (VTA). Glutamate
is also thought to be a large part of this system, it’s excitatory response and NMDA receptors may
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shorten reaction time for responses to stimuli that predict reward (Gorwood, 2008). All of these
neurotransmitters can affect the reward system and therefore play a role in anhedonia.
Depression is thought to follow the diathesis-stress model and is caused by genetic vulnerability
and exposure to stressful situations. Anhedonia may be due to the same factors. A recent study by Ren
et al. (2018), identified the transcription factor NAPS3 in those with anhedonia, indicating there may be
a genetic correlate.
Experiments
In order to examine a new route of treatment for those with extremely resistant forms of
depression, Schlapfer et al. (2008) experimented with an anhedonia treatment where they implanted
deep brain stimulation (DBS) electrodes in the nucleus accumbens. This paper is a somatic intervention
because they are using electrical stimulation in the brain to examine changes in their anhedonic
behavior. The participants were three MDD patients with extremely resistant forms of depression where
psychotherapy, pharmacotherapy, and ECT had all failed. Utilizing PET scans, brain metabolism was
assessed one week before the stimulation and one week after stimulation onset. The electrodes had
been planted bilaterally in the ventral striatum and each had four contacts: shell and core of the nucleus
accumbens in addition to the ventral and medial internal capsule. The automatic stimulator was
randomly switched on and off (in a double-blind manner) throughout the trial and took clinical ratings of
depression. The independent variable was DBS or no DBS and the dependent variables were the changes
in clinical ratings of depression and the change in brain metabolism. The controls for the study was
comparing the DBS off to on, a placebo trial, and PET scans before the DBS (Schlapfer et al., 2008).
The results were that for all three patients the clinical ratings improved when the DBS was on
and the clinical ratings worsened when the DBS was off. The PET data, after one week of stimulation,
shows that brain metabolism had increased in the bilateral ventral striatum, bilateral, dorsolateral, and
dorsomedial prefrontal cortex, cingulate cortex, and bilateral amygdala which usually has a decreased
activity in depression and anhedonia. Decreased brain metabolism was found in the ventromedial and
ventrolateral prefrontal cortex, dorsal caudate nucleus, and thalamus which is usually hypermetabolic in
depression and anhedonia (Figure 3). This method had reduced anhedonia and depression
symptomology and had no side effects. The researchers think that more targeted treatment approaches
could be very useful for treatment-resistant patients.
The ethics of this research could be quite controversial. The participants were humans who had
to undergo surgery to implant the electrodes, complications with this process could have been
dangerous. The electrodes were randomly turned on and off to examine changes in their depression
scores, this change could have had a large impact on the emotional well-being of the participants. Yet,
these patients are treatment-resistant and this research did help their symptoms and could help others,
so for that reason, I do think the research does help with the knowledge in this area and could benefit
society.
For the behavioral intervention paper, Keller et al. (2013) studied trait anhedonia in healthy
adults by exposing them to music stimuli while in an fMRI. This is a behavioral intervention because
participants took part in the behavior of listening to music and then the effects of that music were
analyzed within the brain. Utilizing healthy individuals creates an improved way to examine anhedonia
separate from psychiatric disorder symptoms. Participants took a questionnaire to determine their
levels of trait anhedonia. Then they were asked to listen to music in an fMRI to pinpoint connectivity for
anhedonia. Following that the music was replayed and they were asked to rate the music on its
pleasantness. The researchers used unpleasant scrambled music clips, to confirm that connectivity was
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not due to auditory processing. The independent variable was the music played and the dependent
variable was the brain activity. The control used in the study was the scrambled unpleasant music
(Keller, et al. 2013).
Trait anhedonia was negatively correlated with pleasantness ratings of the musical stimuli,
demonstrating that the higher a participant scored in anhedonia, the less pleasant they thought the
music was. Trait anhedonia was also negatively correlated with activation of brain structures important
to reward processing (nucleus accumbens, basal forebrain, hypothalamus) (Figure 4) and brain
structures related to salient emotional stimuli (anterior insula and orbitofrontal cortex). There was also
lower connectivity between brain structures involved in regulating emotional reactivity to hedonic
stimuli (nucleus accumbens, VTA, and paralimbic areas (Keller et al., 2013).
Overall, this research design was ethical and no participants were treated unfairly or harmed in
any way. I do think it implicated a lot of structures already thought to play a role in anhedonia, but it
does reinforce that these patterns occur aside from psychiatric disorders. I think this research design is
ethical and does help to better understand anhedonia specifically and find new ways to treat it.
To analyze the protein expression of hippocampal serotonin transporters (5-HTT) within the
brain, researchers used stress to elicit anhedonic behavior. 5-HTT regulates the extracellular
concentration of serotonin, therefore influencing neurotransmission. Researchers mimicked depression
by exposing mice to unpredictable chronic mild stress (UCMS) for ten weeks, after six weeks the mice
were tested for anhedonia through sucrose preference and were then divided into anhedonic and
nonanhedonic groups. Half of each group (anhedonic and nonanhedonic) were treated with fluoxetine, a
common antidepressant, and the other half of each group were treated with saline. Hippocampal 5-HTT
proteins were measured at baseline, the end of the 6 weeks, and again after the drug treatment. In
order to determine the behavioral state and the drug’s therapeutic efficacy, researchers assessed the
mice’s sucrose preference, the physical state of their coat, and their body weight. The independent
variables were the UCMS stress that led to anhedonic and non-anhedonic groups and the FLX or saline
treatments; the dependent variable was the 5-HTT protein expression and stress-induced behavior. The
controls for this experiment was an actual control group to compare stressed mice to and a saline
treatment group (Tang, Lei, Sun, Liu, & Zhao, 2013).
The change in hippocampal 5-HTT protein expression was correlated with stress-induced
behaviors. A decrease of 5-HTT was associated with a hedonic state and an increase in 5-HTT was
associated with a non-anhedonic state. After the drug treatment, the group that responded positively to
fluoxetine had increased the sucrose preference in those with anhedonia and matched the control
group’s sucrose preference (Figure 5). Those who did not respond to the fluoxetine treatment still had a
decreased sucrose preference. Researchers suggest that different changes in 5-HTT protein expression
may contribute to variations in vulnerability to develop anhedonia. These results indicate that
decreased levels of hippocampal 5-HTT must be a distinct change in anhedonia and that fluoxetine can
treat this change but only in half of the subjects (Tang et al., 2013).
Since this research utilized mice instead of humans, it is an ethical way to examine anhedonia.
This research helps to better understand serotonin’s role in depression and allows more understanding
of current antidepressant medication and future treatment options.
Anhedonia in Counseling
Understanding the behavior of anhedonia is incredibly important to those in the counseling or
clinical psychology fields. Anhedonia, although mostly associated with depression, is also characteristic
of other psychological disorders like schizophrenia. Information on the neurobiology behind anhedonia
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can help me to create effective treatment plans and have a better understanding of my patients’ ability
to commit to a treatment plan due to their lack of motivation/pleasure.
McMakin et al. (2012) researched how anhedonia can affect SSRI treatment-resistant depression
patients’ time to remission. Youth patients who were SSRI treatment-resistant were used to determine
what symptoms of depression could predict remission times. Patients were randomized into either a
group with a medication change (different than what they had previously been resistant to) or a group
with a medication change and CBT. They then analyzed how many days people were symptom-free and
how long it took to reach that point. Five depression symptom dimensions were examined: reported
depressed mood, anhedonia, somatic symptoms, morbid thoughts, and observed depression. The
independent variable was the two groups and the five different depression symptom dimensions; the
dependent variable was the symptom severity, the time to remission, and the number of days
depression-free (McMakin et al., 2012).
Out of the five dimensions, only anhedonia predicted both a longer time to remission and fewer
days with depression symptoms. Anhedonia predicted these results better than the Children’s
Depression Rating Scale-Revised (CDRS-R), therefore the researchers suggest that anhedonia may be a
helpful tool in determining a patient’s time to remission. There were no significant interactions between
CBT and the symptoms which suggest that the current CBT does not address anhedonic symptoms well.
The researchers also suggest that perhaps anhedonia is slowing remission and can be a target for future
interventions (McMakin et al., 2012).
Conclusion
While researching anhedonia, I found the complexity and interconnectedness of brain structures
very interesting. For example, in the research study by Schlaepfer et al. (2008) the DBS in the nucleus
accumbens was able to affect other brain regions’ role in depression due to their connectivity. I also
found it interesting that the research on 5-HTT protein expression demonstrated that even in a mouse
population an SSRI like fluoxetine only works in about 50% of the population (Tang et al., 2013). Overall,
I learned that anhedonia is much more complex than I had previously thought and many neurobiological
underpinnings can affect someone’s pleasure or motivation.
Someone in my field would benefit from understanding how important anhedonia is in
depression symptomology. It is also important for counselors to stay updated on research like this to
improve their ability to help their patients. They may benefit in learning of new treatment for anhedonia
due to SSRI-resistance and research within DBS. Perhaps they could create changes within their CBT
practice that could make changes that focus on not only fixing negative problems but also reinforcing
positive ones like pleasure and motivation. Information on the brain structures, circuitry, and
neurotransmission could help them to better understand the disorder they are working with.
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References

Gorwood P. (2008). Neurobiological mechanisms of anhedonia. Dialogues in Clinical Neuroscience, 10(3),

291–299.

Keller, J., Young, C. B., Kelley, E., Prater, K., Levitin, D. J., & Menon, V. (2013). Trait anhedonia is

associated with reduced reactivity and connectivity of mesolimbic and paralimbic reward

pathways. Journal of Psychiatric Research, 47(10), 1319–1328. doi:

https://doi.org/10.1016/j.jpsychires.2013.05.015

McMakin, D. L., Olino, T. M., Porta, G., Dietz, L. J., Emslie, G., Clarke, G., Wagner, K. D., Asarnow, J. R.,

Ryan, N. D., Birmaher, B., Shamseddeenm W., Mayes, T., Kennard, B., Spirito, A., Keller, M.,

Lynch, F. L., Fickerson, J. F., & Brent, D. A. (2012). Anhedonia predicts poorer recovery among

youth with selective serotonin reuptake inhibitor treatment–resistant depression. Journal of the

American Academy of Child & Adolescent Psychiatry, 51(4), 404–411. doi:

https://doi.org/10.1016/j.jaac.2012.01.011

NIMH. (2019, February). Major Depression. Retrieved from

https://www.nimh.nih.gov/health/statistics/major-depression.shtml

Ren, H., Fabbri, C., Uher, R., Rietschel, M., Mors, O., Henigsberg, N., Hauser, J., Zobel, A., Maier, W.,

Dernovsek, M. Z., Souery, D., Cattaneo, A., Breen, G., Craig, I. W., Farmer, A. E., McGuffin, P.,

Lewis, C. M., & Aitchison, K. J. (2018). Genes associated with anhedonia: A new analysis in a

large clinical trial (GENDEP). Translational Psychiatry 8, 150. doi:

https://doi.org/10.1038/s41398-018-0198-3

Schlaepfer, T., Cohen, M., Frick, C., Kosel, M., Brodesser, D., Axmacher, N., Young Joe, A., Kreft, M.,

Lenartz, D., & Sturm, V. (2008). Deep Brain Stimulation to Reward Circuitry Alleviates Anhedonia
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in Refractory Major Depression. Neuropsychopharmacology, 33, 368–377. doi:

https://doi.org/10.1038/sj.npp.1301408

Tang, M., Lei, J., Sun, X., Liu, G., & Zhao, S. (2013). Stress-induced anhedonia correlates with lower

hippocampal serotonin transporter protein expression. Brain Research, 1513, 127–134. doi:

https://doi.org/10.1016/j.brainres.2013.03.042
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Figures

Figure 1: Circuitry Impacted in Anticipatory Pleasure/Reward

Figure 1: This visual I believe is from a paper on anhedonia in Schizophrenia, but highlights the same
structures and circuits important in depression. The location of the thalamus in this image is purely to
make the connectivity simpler. Nucleus accumbens (N.Acc), globus pallidus (GP), ventral pallidus (VP),
substantia nigra pars compacta (SNpc), ventral tegmental area (VTA), orbitofrontal cortex (OFC),
dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC).
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Figure 2: Pleasure Related Brain Structures

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Figure 3: PET Brain Metabolism of Anhedonia Implicated Structures (Schlaepfer et al., 2008)

Figure 3: This figure, showing PET data one week after the start of DBS to the nucleus accumbens,
indicates the changes in metabolism. The yellow indicates increases in brain metabolism and the blue
indicates decreases in brain metabolism. This figure identifies an increase in activity in the nucleus
accumbens (lnacc and rnacc) and the dorsal cingulate cortex (dCC). In anhedonia, these structures
usually have a decreased level of activity, so this increase indicates that the DBS treatment did increase
the activity within these regions and corrected the deficits of depression. There was a decrease in
metabolism in the medial prefrontal cortex (mPFC). Within anhedonia this structure is known to be
hypermetabolic, demonstrating that the DBS treatment helped to lower the activity, which most likely
also contributed to the depression relief. The right side of this figure indicates the before stimulation
and after stimulation results (normalized PET units) for each of the three participants. This also exhibits
the increase in metabolism within the right and left side of the nucleus accumbens and the dorsal
cingulate cortex. It also shows a decrease in metabolism within the medial prefrontal cortex.
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Figure 4: fMRI of the Mesolimbic Reward System and Limbic Regions (Keller et al., 2013)

Figure 4: This figure indicates the negative correlations found within these specific structures and trait
anhedonia. This means that those with a high score for trait anhedonia also had low levels of activity in
the nucleus accumbens (NAc), the hypothalamus, and the basal forebrain.
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Figure 5: Western Blot Data of 5-HTT and Fluoxetine Treatment of Anhedonia (Tang et al., 2013)

Figure 5: This figure utilized Western Blots to determine hippocampal 5-HTT protein expression due to
UCMS (unpredictable chronic mild stress) and FLX (fluoxetine) treatment. Figure 5A analyzes the
baseline levels of 5-HTT for both the group of mice that will be the control group and the group that will
be stressed. We can analyze no significant difference in the Western Blot image or the qualitative graphs
between the two groups in terms of 5-HTT levels. Figure 5B is after six weeks of UCMS, there is a visible
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difference in the Western Blot indicating a difference in 5-HTT protein levels. The graph shows this
difference, non-anhedonic mice had a significant increase in the 5-HTT protein expression compared to
the control group. The anhedonic mice had a significant decrease in 5-HTT expression compared to the
control group. Figure 5C analyzed the 5-HTT protein expression after the FLX treatment or saline
treatment. Again, we see that the non-anhedonic mice had an increase in 5-HTT expression compared to
control in both the FLX treatment group and the saline group and the control saw no change in 5-HTT
expression. These results indicate that the non-anhedonic group and the control group were unaffected
by FLX treatment. The anhedonic mice who weren’t FLX treatment-resistant (FLX+), the treatment had
returned their levels of 5-HTT expression to mimic those in the control group. Anhedonic mice that were
FLX resistant (FLX-) continued to have a decrease in 5-HTT protein levels compared to control. The saline
group mimicked the results before treatment, where non-hedonic had an increase from control and
anhedonic mice had a decrease from control.

*P<0.05 vs. non-stressed controls by one-way ANOVA; ♯P<0.05 vs. non-stressed controls; §P<0.05 vs.
saline-treated anhedonic mice by simple effects post hoc analysis after a significant interaction in the
two-way ANOVA; @P<0.05 vs. FLX(−) mice by one-way ANOVA.
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