Jumpstarting emotional flatlining in patients living with MDD

Jumpstarting emotional flatlining in patients living with MDD

Anhedonia, defined as a noticeable diminished interest or pleasure in all, or almost all, activities, is one of the key features of major depressive disorder (MDD). Anhedonia is considered a major suicide risk factor. Up to 70% of patients living with MDD experience anhedonia.1

Anhedonia is also common in patients living with other psychiatric disorders.1,2

According to Serretti, the definition of anhedonia include a broad spectrum of deficits in reward processing such as interest, motivation, effort expenditure, valuation, reward anticipation, learning, pleasure, and satiation.1

Categorisation of anhedonia

Anhedonia can be subcategorised as:1

• State anhedonia: Can manifest as a reduced capacity to find pleasure –individuals may cease to enjoy activities that were once pleasurable, particularly evident during acute MDD episodes.

• Trait anhedonia: Some patients may exhibit a persistent and general impairment in experiencing pleasure, irrespective of temporal considerations. This trait may be associated with conditions like dysthymia or substance abuse.

• Social anhedonia: Defined as getting little or no pleasure from interpersonal situations.

• Physical anhedonia: Defined as getting little or no pleasure from non-social physical sensations like smell, taste, touch, or sound.

The disease course of anhedonia is not stable and may change, depending on the phase of the disorder and may decrease or disappear completely after recovery.1

Anhedonia and suicide risk

Suicide is a growing public health crisis, contributing to >700 000 deaths globally. Suicide is currently the second leading cause of mortality among individuals aged 15- to 24-years. A meta-analysis conducted by Gillissie et al shows a substantial and moderate correlation between anhedonia and suicidality in both general and psychiatric populations (9.61% and 10.24%, respectively).2

The neurophysiological and genetic basis of MDD and anhedonia

Multiple factors contribute to MDD. It has been linked to a combination of genetic, environmental, biological, and physiological factors. The neurophysiological basis of anhedonia has been investigated in numerous studies.1

These studies found that the prefrontal cortex, which include the ventromedial and dorsolateral regions, plays a crucial role in reward processing and decision-making. A key mechanism underlying anhedonia involves striatal hypoactivation for anticipatory anhedonia (an inability to predict the future experience of pleasure as well as lower motivation to act toward achieving pleasure) and prefrontal areas for consummatory anhedonia (a lack of pleasure when participating in an activity that others would consider gratifying).1

Various brain regions, including the nucleus accumbens, striatum, ventral pallidum, ventral tegmental area, amygdala, insula, anterior cingulate cortex, orbitofrontal cortex, and prefrontal cortex, have been implicated in studies, highlighting the multifaceted nature of reward deficits.1

Dopamine has been extensively studied as the neurotransmitter most associated with anhedonia, with clinical support for its role in regulating anticipation, motivation, effort, and learning. Furthermore, other neurotransmitters such as serotonin (5HT), epinephrine, opioids, glutamate, gamma-aminobutyric acid (GAMA), and acetylcholine may modulate consummatory pleasure and motivation.1

A genome-wide analysis identified 11 loci explaining 5.6% of anhedonia, with polygenic risk scores showing promise in predicting an individual’s risk for developing the condition based on their genetic makeup.1

These scores were associated with structural brain changes, linking genetic risk to brain white matter integrity and volumes of regions involved in reward and pleasure processing.1

Epigenetic modifications, chemical changes to DNA influencing gene expression without altering the sequence, have also been explored in relation to anhedonia. Reports suggest that epigenetic modifications to genes involved in reward processing and mood regulation are associated with anhedonia.1

How do you treat MDD?

Guidelines for the treatment of MDD recommend the following interventions based on the severity of the disorder:3

• Initiate monotherapy with either cognitive behavioural therapy (CBT) or a second-generation antidepressant as the primary treatment for patients in the acute phase of moderate to severe MDD.

• Consider combination therapy with CBT and a second-generation antidepressant as an alternative initial treatment for patients in the acute phase of moderate to severe MDD.

• The decision between monotherapy and combination therapy should be individualised, considering factors such as potential treatment benefits, adverse effects, cost, feasibility, specific symptoms (eg insomnia, hypersomnia, appetite fluctuations), comorbidities, concomitant medication use, and patient preferences.

• Consider monotherapy with cognitivebehavioural therapy as the initial treatment for patients in the acute phase of mild MDD.

• For patients in the acute phase of moderate to severe MDD who do not respond to initial treatment with an adequate dose of a second-generation antidepressant, consider the following options:

- Switching to or augmenting with CBT

- Switching to a different second-generation antidepressant or augmenting with a second pharmacologic treatment.

Conclusion

Anhedonia, a prominent feature of MDD, poses a substantial suicide risk, affecting up to 70% of patients. The multifaceted nature of anhedonia includes anticipatory and consummatory components, with various subcategories like state, trait, social, and physical anhedonia. Anhedonia correlates significantly with suicidality, emphasising its role as a fundamental risk factor. The treatment landscape for MDD involves various interventions, with second-generation antidepressants. References are available on request. SF