Motivation and Pleasure in Depression

Anhedonia, the loss of interest or pleasure in response to stimuli that were previously experienced as rewarding, is one of the core symptoms of depression. Using neurobiological findings, Michael Treadway and David Zald of Vanderbilt University have proposed distinctions among aspects of anhedonia, which may be clinically useful. They separate a reward-based component, deficient wanting, or motivation, from reduced ability to experience pleasure, which they call deficient “liking, or consummatory anhedonia.” They refer to a 1987 comment by Donald Klein that “many patients with depression and anhedonia appeared to enjoy rewards that were readily available, yet complained bitterly about feeling no desire to obtain them.” In addition, Treadway and Zald propose a “decisional anhedonia” related to problems with reward-based decision-making.

As I have noted before, depression research is plagued by symptom heterogeneity—two patients can meet DSM 5 criteria for major depression while sharing only one of the nine defining symptoms. Comorbidity is frequent, especially with anxiety disorders. Etiological heterogeneity is also likely—depression may be a “final common pathway” of contributions from genetics, early life and current stress, and medical and pharmacological issues. Treadway and Zald's proposal is a step toward untangling this confusing symptomatic and etiological picture.

The authors note two qualifications. First, and this applies to all neurobiological research, is the “streetlight effect,” the tendency to look where the looking is easiest. Even the latest neuroimages are of low resolution compared to the intricacies of the brain, where synapses are measured in nanometers (billionths of a meter) and a nerve impulse lasts about a millisecond. As researchers attempts to answer theoretical questions and fill in the blanks of our understanding, they are both driven and limited by the rapid deployment of technologies such as radio-isotopic tagging and immune-labeling. As techniques become available, they are applied wherever they are useful, which leads to detailed understanding of some processes as well as large areas of ignorance.

The kinds of information available from human and animal studies further distort the picture. Animal research relies on observations of behavior, while people can report subjective states and thoughts. Genetic manipulation, lesioning, and placement of electrodes to record from or stimulate brain cells are acceptable in animals but, but their use is severely limited in humans. Significant deception of human subjects and withholding treatment from ill patients are considered unethical. The result, Treadway and Zald note, is that research on humans has tilted toward pleasure and its mechanisms, while animal research has emphasized motivation and reinforcement.

Although many clinical and laboratory assessment instruments, including the Structural Clinical Interview for DSM Axis-I Disorders (SCID), do not distinguish between motivation and pleasure, the authors argue that we know enough about their neurochemistry and circuitry to consider them separate phenomena.

Several animal models show that dopamine has a strong role in reward and relatively little in pleasure. Dopaminergic neurons in the substantia nigra and ventral tegmental area of the midbrain ascend in three pathways to the forebrain. The nigrostriatal tract, which psychiatrists may recognize as the site of neurologic side effects of dopamine-blocking antipsychotic medication and Parkinson’s disease, is involved in motor control and habit learning. The mesolimbic pathway terminates in the nucleus accumbens, amygdala, and hippocampus and is associated with associative learning, reward motivation, and reinforcement. The mesocortical tract densely innervates the anterior cingulate cortex and also the orbital frontal cortex, medial prefrontal cortex, and insula, and is involved with working memory, attention, and inhibitory control. The midbrain dopaminergic neurons maintain steady state “tonic” activity and also fire in bursts; the latter requires both excitatory and inhibitory input from several brain regions. In the striatum, dopamine modulates the sensitivity of post-synaptic neurons, acting primary on a several G-protein coupled receptors. Thus dopaminergic cells, which comprise less than one percent of the brain's neurons, are involved in complex ways in the regulation and operation of several systems central to the brain’s function.

Animal research using methodology of brain lesions, genetic engineering, and pharmacological blockade of receptors consistently shows that disruption of the mesolimbic dopamine tract interferes with “wanting” but not with “liking.” Research in depressed patients has advanced more slowly, and the findings are more complex. Early work found reduced levels of the primary dopamine metabolite in cerebrospinal fluid of depressed patients, suggesting reduced dopaminergic tone. Various antidepressant drugs, including selective serotonin reuptake inhibitors (SSRI’s), increase dopamine receptor availability in the nucleus accumbens. Dopamine agonists, including bromocriptine and pramipexole, as well as dopamine reuptake inhibitors like methylphenidate and bupropion, have antidepressant properties. At the time of Treadway and Zald’s review (2011) the imaging data was unclear, but some studies found reduced dopamine binding in depressed patients, particularly those with anhedonic symptoms.

Certain genetic polymorphisms related to dopamine function increase the risk of depression. Depression is also associated with elevated levels of the stress hormone cortisol and decreased availability of brain-derived neurotrophic factor (BDNF,) as well as neuronal degeneration in the hippocampus and medial prefrontal cortex. Glucocorticoids like cortisol modify the firing of dopaminergic neurons, and the hippocampus and medial prefrontal cortex are important regulators of both the mesolimbic and mesocortical dopamine pathways.

According to Treadway and Zald, “liking” is mediated primarily by endogenous opioids. Two “hotspots,” which are thought to be the origin of pleasure responses, have been identified: the shell of the nucleus accumbens, and the ventral pallidum, a basal ganglia structure which is part of the “limbic loop” regulating motivation, behavior, and emotions.

They go on to discuss subregions of the ventromedial prefrontal cortex which process rewarding stimuli, connecting stimuli with rewards, anticipating rewards, and attributing affective values to rewards. The anterior cingulate cortex appears to be involved in making cost-benefit evaluations of reward choices. In addition, lesion studies in animals show involvement of the amygdala in evaluating rewards.

Studies of the role of opioids in depression have been equivocal, at least at the time of Treadway and Zald’s review. (There is more recent interest in using specialized opioid preparations to treat depression.) Psychological experiments have found increased activity in the rostral anterior cingulate cortex in response to positively-valenced affective stimuli in depressed patients compared to controls. In contrast, depressed individuals have blunted amygdala responses to positive stimuli.

One problem with extending findings from animal studies to human depression is that anhedonia is generally conceptualized as an ongoing mood-like phenomenon, while animal research has looked at short-term decisions reflected in behavior. Treadway and Zald suggest that impaired motivation in humans can be thought of as an ongoing series of decisions. Reviewing animal studies, the authors propose a cost-benefit decision-making network comprising the nucleus accumbens, anterior cingulate cortex, amygdala, and mesolimbic dopaminergic neurons. At the time of the review, only a few imaging studies had looked at the applicability of this model to depression in humans, and their results were inconsistent.

The authors recommend revising interview protocols such as the SCID to separate motivational from hedonic symptoms. They go on to discuss the implications of this emerging research for treating depressed patients, highlighting a type of cognitive-behavioral therapy (CBT) called Behavioral Activation, which conceptualizes distorted thoughts as ruminative behavior. The idea is to help patients identify rewarding and non-rewarding behaviors and to make choices likely to increase positive experiences. They cite evidence of its effectiveness compared to traditional CBT. Imaging studies showed activation of the striatum during successful treatment, while CBT tends to show reduced sensitivity of the amygdala to negative stimuli, suggesting the treatments work in different ways.

They also discuss dopaminergic pharmacological treatments for patients with motivational anhedonia. On the basis of animal data, they hypothesize that bupropion may be particularly effective for patients with motivational anhedonia. The note that pramipexole may also be useful for such patients, while the psychostimulants, although they increase dopamine activity, are not, with the exception of special populations such as geriatric patients.

Treadway and Zald end with the comment that their effort to separate motivational from consummatory anhedonia is an example of using emerging knowledge of neurobiological systems to refine our clinical definition of a symptom. This approach is quite appealing. It can work both ways—from the clinical to the biological, as in the authors’ separation of the symptom of anhedonia into biologically-grounded concepts of motivation, pleasure, and conditioned learning. It is also possible to start with biological understanding of a brain system, such as the reward system, and looking at its abnormalities in clinical symptoms and disorders.

I will be paying more attention to the vicissitudes of motivation and pleasure as I seek to understand the experiences of my depressed patients. I would need more information to change my prescribing in favor of bupropion or pramipexole for patients with motivational problems, since the history of selecting antidepressants based on clinical symptoms has generally not been good.

Further reading:

Treadway MT, Zald DH. Reconsidering Anhedonia in Depression: Lessons from Translational Neuroscience. Neurosci Biobehav Rev. 2011; 35:537-555.

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