Anhedonic depression as a novel, mechanism-based subtype of depression - Treatment implications for precision psychiatry

Anhedonia is the inability to experience pleasure from, or the lack of motivation to carry out usually enjoyable activities. Significant anhedonia occurs in up to 40% of all depression and is associated with functional impairment and treatment resistance to traditional medications. To reliably capture the various aspects of anhedonia, valid assessment scales are necessary. Recently the Dimensional Anhedonia Rating Scale (DARS) was proposed as a new way to better tap into the different facets of anhedonia. This is a dynamic scale that measures desire, motivation, effort and consummatory pleasure across hedonic domains. This rating scale has not yet been used to evaluate the “anti-anhedonic” efficacy of any intervention, though there is a clinical need to this type of studies.

Dopamine, in the mesolimbic neuronal pathway, is the neurotransmitter most involved in the ability to experience pleasure (“hedonia”) and in determining motivational drive. The importance dopamine and of the mesolimbic circuit in anhedonia and motivation has been demonstrated in both animal studies and human functional magnetic resonance imaging (fMRI) studies. There are multiple types of receptors for dopamine in the brain. The dopamine receptor D3 is expressed in phylogenetically older regions of the brain, for example structures important in the mesolimbic pathway. The DRD3 gene has a polymorphic site on where the amino acid serine (Ser) is changed to glycine (Gly). Dopamine has a 4 5 times higher affinity for the Gly-variant compared to the Ser-variant leading to increased downstream effects of dopamine binding to the receptor. One recent study has shown that people with the Gly-variant has an increased dopamine release in the reward pathway in brain after a reward and linked to symptoms of anhedonia in patients diagnosed with depression. Hence, dopamine receptor D3 polymorphism could be a vulnerability factor to develop anhedonic depression.

It is possible to adjust dopamine D3-signaling by drugs targeting dopamine receptors. An interesting candidate drug in this respect is pramipexole, a dopamine receptor agonist with high affinity for the D3 receptor. This is an established treatment for Parkinson’s disease (PD) and restless legs syndrome. Pramipexole has shown an antidepressant effect in PD patients, partly independent of motor symptom improvement. Anhedonia and lack of motivation are common symptoms in PD that often improve with pramipexole. Only a few Randomized Controlled Trials (RCTs) have tested the efficacy of pramipexole in depression, and results have not been robust enough to allow for clinical recommendations. Recently, Fawcett et al published a summary of 42 case reports of patients with uni- (n=24) and bipolar (n=18) depression treated with add-on
pramipexole. This was a highly treatment resistant sample with a mean number of failed antidepressant trials of 6, and several patients had not responded to ECT. Remarkably, 76% of these patients showed a meaningful clinical response with pramipexole that persisted over an average follow-up time of 16 months. Although striking and potentially clinically impactful, these findings by need to be confirmed in a placebo-controlled RCT before any clinical recommendations can be made.

So far, most studies have investigated how dopaminergic signaling within the mesolimbic pathway mediates anhedonia and related symptoms. Less focus has been paid to peripheral, non-CNS, inputs to the dopaminergic reward circuitries that could potentially influence dopaminergic neuron
responsivity and thereby generate anhedonia symptoms. Accumulating evidence suggests that the behavioral sequelae of inflammation, including motivational anhedonia and alterations in reward-seeking behavior (c.f. “sickness behavior”), are a direct consequence of the impact of cytokines on mesolimbic dopamine signaling. For instance, fMRI-studies of depressed patients report a
correlation between peripheral, low-grade inflammation (assessed by high-sensitivity C-reactive protein (hs-CRP)) and anhedonia mediated via decreased resting-state functional connectivity in the reward circuit. Moreover, various types of immune challenges (to healthy volunteers, patients with hepatitis or animals) triggers motivational anhedonia, a blunted response to reward anticipation in the ventral striatum, and decreased striatal dopamine release and availability.