madman
Super Moderator
Pharmacological Treatments for Anhedonia (2022)
Matthew E. Klein, Ariela Buxbaum Grice, Sahil Sheth, Megan Go, and James W. Murrough
Abstract
Anhedonia – the reduced ability to experience or respond to pleasure – is an important symptom domain for many psychiatric disorders. It is particularly relevant to depression and other mood disorders and it is a diagnostic criterion of a major depressive episode. Developing safe and effective pharmacological interventions for anhedonia is a critical public health need. The current chapter will review the state of the field with respect to both the efficacy of currently available pharmacotherapies for anhedonia and the recent clinical research focusing on new brain targets, including the kappa-opioid receptor and the KCNQ2/3 receptors. The evidence for the anti-anhedonic effects of ketamine and psychedelic agents will be reviewed, as well.
Anhedonia is defined as: “markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day” (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-V]; American Psychiatric Association, 2013). Characterized by a reduced motivation to engage in pleasurable activities or an inability to experience pleasure, anhedonia is a common feature of many psychiatric disorders, including major depressive disorder (MDD), substance use disorders, psychotic disorders, post-traumatic stress disorder (PTSD), and personality disorders (Treadway and Zald 2011). The transdiagnostic nature of anhedonia and its prevalence across a range of psychiatric disorders encourages an understanding of anhedonia as its own psycho-biological process, which may be present alongside diagnosable psychiatric disorders, but has specific neural substrates underlying its pathology (Husain and Roiser 2018; Zhang et al. 2016). It follows, therefore, that pharmacologic treatment targeting anhedonia should consider the unique neurobiological substrates of anhedonia.
Anhedonia is particularly relevant to depressive disorders. Considered a core feature of the disorder, anhedonia is reported by 40–75% of individuals with MDD (Buckner et al. 2008; Pelizza and Ferrari 2009). The presence of anhedonia in association with MDD is clinically important, as anhedonic symptoms are a predictor of poorer treatment response to selective serotonin reuptake inhibitors (SSRIs) and worse functional outcomes, including increased risk of suicide (Spijker et al. 2001; Vrieze et al. 2013; Vinckier et al. 2017; McMakin et al. 2012; Winer et al. 2014; Fawcett et al. 1990). First-line treatments for MDD (e.g., SSRIs) have shown mixed efficacy in the treatment of anhedonia. While a positive treatment response with respect to overall depressive symptoms is generally associated with improved ability to experience pleasure, there are many cases in which anhedonic symptoms persist, even as other mood-related symptoms are restored (Nutt et al. 2007; Whitton et al. 2016). There is, in fact, the potential for antidepressants (particularly SSRIs such as citalopram and fluoxetine) to exacerbate levels of anhedonia due to common side effects like emotional blunting, thereby leaving patients with a greater symptomatic burden (McCabe et al. 2010; Price et al. 2009).To improve clinical outcomes, there is a need for anhedonia-specific pharmacological approaches that are able to address these residual symptoms of anhedonia (Cao et al. 2019)
Anhedonia can manifest as deficits in multiple reward-related domains – including motivation, decision making, anticipation, and consummation of reward – each with its own complex pathophysiology (Treadway and Zald 2011). The reward processes involved in anhedonia – reward valuation, motivation, anticipation, and decision making – map to neural circuitry overlapping with the mesocorticolimbic circuit, including the prefrontal cortex (PFC), the anterior cingulate cortex (ACC), and the striatum (Dillon et al. 2014; Keren et al. 2018; Treadway et al. 2012; Wise 1980). The mesocorticolimbic reward circuit, which connects the ventral tegmental area (VTA) and the nucleus accumbens (NAc) and projects onto the PFC, is the primary pathway for processing and modulating reward-seeking behavior (Dunlop and Nemeroff 2007). Normal functioning of reward-related behavior is sustained by the interplay of the striatum and the medial PFC (mPFC) via the dopaminergic transmitter system and restoration of activity in this system may result in antianhedonic effects. Compounds that demonstrate circuit-engagement relating to these pathways could therefore target symptoms of anhedonia by reversing deficits in the underlying biology (Argyropoulos and Nutt 2013). Indeed, this approach is supported by the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) initiative, which prescribes a transdiagnostic and dimensional focus, based on neurobiological pathways, for psychiatric research, rather than a focus on psychiatric syndromes per se (Dillon et al. 2014; Insel et al. 2010).
In this chapter, we will review potential therapeutic interventions for the treatment of anhedonia in the context of mood disorders, with a focus on the clinical pharmacology of interventions, as well as their potential therapeutic efficacy. We will explore clinical trials conducted in adults with mood disorders, in which anhedonia is an endpoint, measured by a standardized anhedonia rating scale such as the Snaith-Hamilton Pleasure Scale (SHAPS) (Snaith et al. 1995). Some clinical trials relating to anhedonia have utilized functional imaging techniques to probe the effects of potential anti-anhedonic pharmacotherapies on the activity within brain regions related to reward processing. We will consider whether evidence supporting the anti-anhedonic effect of a compound is determined by improvement of clinical symptoms specific to anhedonia or by demonstrating circuit-engagement of anhedonia-related brain regions. While pharmacotherapeutics typically target a range of receptors and pathways, we have grouped agents by their primary mechanisms of action for the purpose of this review. Overall, this chapter will present the current state of the field of pharmacologic agents and their putative anti-anhedonic effects.
1 Kappa-Opioid Receptor Antagonists
2 KCNQ Channel Modulators
3 Ketamine
4 Psychedelics
5 Conventional Antidepressants
6 Conclusion
Anhedonia is a transdiagnostic symptom of reduced capacity to experience pleasure or lack of reactivity to pleasurable stimuli; it has core relevance to mood disorders such as MDD and is also associated with many other psychiatric disorders. Anhedonia in the context of MDD is associated with poor functional outcomes, increased suicide risk, and treatment resistance; first-line antidepressant agents appear to have only limited efficacy against anhedonia. Research indicates that anhedonia can arise through dysregulation with brain systems that control response to reward, with the VTA-NAc dopamine system appearing to be of central importance. In this chapter, we reviewed the data available concerning the efficacy of pharmacotherapy for anhedonia, with a focus on depressive disorders. We began by summarizing recent experimental medicine approaches to identify pharmacotherapy targeting anhedonia, including work involving the KOR and the KCNQ2/3 systems. We then reviewed data concerning ketamine, psychedelic agents – such as psilocybin – and, finally, conventional antidepressant agents and agomelatine. While the data for the effects of conventional antidepressants on anhedonia are limited, it is likely that agents with activity at systems other than serotonin will be important for the development of future anti-anhedonic agents. In terms of treatment response prediction, baseline reward processing, and VS DA function were recently reported to be associated with response to the DA drug pramipexole in adults with depression (Whitton et al. 2020). In a separate recent study, baseline reward sensitivity and fronto-striatal resting-state functional connectivity were related to therapeutic response to atypical antidepressant bupropion in adults with depression who had failed to respond to the SSRI, sertraline (Ang et al. 2020). Both of these studies suggest the potential of reward-related behavioral or brain-based biomarkers to predict response to agents that may preferentially target reward systems (i.e., via their DA-related activity). Work in this area is still in its early stages and requires replication. Hopefully, additional research focused on targeting brain systems that mediate reward function will speed the development of safe and effective treatment of anhedonia across psychiatric diagnoses.
Matthew E. Klein, Ariela Buxbaum Grice, Sahil Sheth, Megan Go, and James W. Murrough
Abstract
Anhedonia – the reduced ability to experience or respond to pleasure – is an important symptom domain for many psychiatric disorders. It is particularly relevant to depression and other mood disorders and it is a diagnostic criterion of a major depressive episode. Developing safe and effective pharmacological interventions for anhedonia is a critical public health need. The current chapter will review the state of the field with respect to both the efficacy of currently available pharmacotherapies for anhedonia and the recent clinical research focusing on new brain targets, including the kappa-opioid receptor and the KCNQ2/3 receptors. The evidence for the anti-anhedonic effects of ketamine and psychedelic agents will be reviewed, as well.
Anhedonia is defined as: “markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day” (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-V]; American Psychiatric Association, 2013). Characterized by a reduced motivation to engage in pleasurable activities or an inability to experience pleasure, anhedonia is a common feature of many psychiatric disorders, including major depressive disorder (MDD), substance use disorders, psychotic disorders, post-traumatic stress disorder (PTSD), and personality disorders (Treadway and Zald 2011). The transdiagnostic nature of anhedonia and its prevalence across a range of psychiatric disorders encourages an understanding of anhedonia as its own psycho-biological process, which may be present alongside diagnosable psychiatric disorders, but has specific neural substrates underlying its pathology (Husain and Roiser 2018; Zhang et al. 2016). It follows, therefore, that pharmacologic treatment targeting anhedonia should consider the unique neurobiological substrates of anhedonia.
Anhedonia is particularly relevant to depressive disorders. Considered a core feature of the disorder, anhedonia is reported by 40–75% of individuals with MDD (Buckner et al. 2008; Pelizza and Ferrari 2009). The presence of anhedonia in association with MDD is clinically important, as anhedonic symptoms are a predictor of poorer treatment response to selective serotonin reuptake inhibitors (SSRIs) and worse functional outcomes, including increased risk of suicide (Spijker et al. 2001; Vrieze et al. 2013; Vinckier et al. 2017; McMakin et al. 2012; Winer et al. 2014; Fawcett et al. 1990). First-line treatments for MDD (e.g., SSRIs) have shown mixed efficacy in the treatment of anhedonia. While a positive treatment response with respect to overall depressive symptoms is generally associated with improved ability to experience pleasure, there are many cases in which anhedonic symptoms persist, even as other mood-related symptoms are restored (Nutt et al. 2007; Whitton et al. 2016). There is, in fact, the potential for antidepressants (particularly SSRIs such as citalopram and fluoxetine) to exacerbate levels of anhedonia due to common side effects like emotional blunting, thereby leaving patients with a greater symptomatic burden (McCabe et al. 2010; Price et al. 2009).To improve clinical outcomes, there is a need for anhedonia-specific pharmacological approaches that are able to address these residual symptoms of anhedonia (Cao et al. 2019)
Anhedonia can manifest as deficits in multiple reward-related domains – including motivation, decision making, anticipation, and consummation of reward – each with its own complex pathophysiology (Treadway and Zald 2011). The reward processes involved in anhedonia – reward valuation, motivation, anticipation, and decision making – map to neural circuitry overlapping with the mesocorticolimbic circuit, including the prefrontal cortex (PFC), the anterior cingulate cortex (ACC), and the striatum (Dillon et al. 2014; Keren et al. 2018; Treadway et al. 2012; Wise 1980). The mesocorticolimbic reward circuit, which connects the ventral tegmental area (VTA) and the nucleus accumbens (NAc) and projects onto the PFC, is the primary pathway for processing and modulating reward-seeking behavior (Dunlop and Nemeroff 2007). Normal functioning of reward-related behavior is sustained by the interplay of the striatum and the medial PFC (mPFC) via the dopaminergic transmitter system and restoration of activity in this system may result in antianhedonic effects. Compounds that demonstrate circuit-engagement relating to these pathways could therefore target symptoms of anhedonia by reversing deficits in the underlying biology (Argyropoulos and Nutt 2013). Indeed, this approach is supported by the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) initiative, which prescribes a transdiagnostic and dimensional focus, based on neurobiological pathways, for psychiatric research, rather than a focus on psychiatric syndromes per se (Dillon et al. 2014; Insel et al. 2010).
In this chapter, we will review potential therapeutic interventions for the treatment of anhedonia in the context of mood disorders, with a focus on the clinical pharmacology of interventions, as well as their potential therapeutic efficacy. We will explore clinical trials conducted in adults with mood disorders, in which anhedonia is an endpoint, measured by a standardized anhedonia rating scale such as the Snaith-Hamilton Pleasure Scale (SHAPS) (Snaith et al. 1995). Some clinical trials relating to anhedonia have utilized functional imaging techniques to probe the effects of potential anti-anhedonic pharmacotherapies on the activity within brain regions related to reward processing. We will consider whether evidence supporting the anti-anhedonic effect of a compound is determined by improvement of clinical symptoms specific to anhedonia or by demonstrating circuit-engagement of anhedonia-related brain regions. While pharmacotherapeutics typically target a range of receptors and pathways, we have grouped agents by their primary mechanisms of action for the purpose of this review. Overall, this chapter will present the current state of the field of pharmacologic agents and their putative anti-anhedonic effects.
1 Kappa-Opioid Receptor Antagonists
2 KCNQ Channel Modulators
3 Ketamine
4 Psychedelics
5 Conventional Antidepressants
6 Conclusion
Anhedonia is a transdiagnostic symptom of reduced capacity to experience pleasure or lack of reactivity to pleasurable stimuli; it has core relevance to mood disorders such as MDD and is also associated with many other psychiatric disorders. Anhedonia in the context of MDD is associated with poor functional outcomes, increased suicide risk, and treatment resistance; first-line antidepressant agents appear to have only limited efficacy against anhedonia. Research indicates that anhedonia can arise through dysregulation with brain systems that control response to reward, with the VTA-NAc dopamine system appearing to be of central importance. In this chapter, we reviewed the data available concerning the efficacy of pharmacotherapy for anhedonia, with a focus on depressive disorders. We began by summarizing recent experimental medicine approaches to identify pharmacotherapy targeting anhedonia, including work involving the KOR and the KCNQ2/3 systems. We then reviewed data concerning ketamine, psychedelic agents – such as psilocybin – and, finally, conventional antidepressant agents and agomelatine. While the data for the effects of conventional antidepressants on anhedonia are limited, it is likely that agents with activity at systems other than serotonin will be important for the development of future anti-anhedonic agents. In terms of treatment response prediction, baseline reward processing, and VS DA function were recently reported to be associated with response to the DA drug pramipexole in adults with depression (Whitton et al. 2020). In a separate recent study, baseline reward sensitivity and fronto-striatal resting-state functional connectivity were related to therapeutic response to atypical antidepressant bupropion in adults with depression who had failed to respond to the SSRI, sertraline (Ang et al. 2020). Both of these studies suggest the potential of reward-related behavioral or brain-based biomarkers to predict response to agents that may preferentially target reward systems (i.e., via their DA-related activity). Work in this area is still in its early stages and requires replication. Hopefully, additional research focused on targeting brain systems that mediate reward function will speed the development of safe and effective treatment of anhedonia across psychiatric diagnoses.
