Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder

Abstract

The serotonin deficit hypothesis explanation for major depressive disorder (MDD) has persisted among clinicians and the general public alike despite insufficient supporting evidence. To combat rising mental health crises and eroding public trust in science and medicine, researchers and clinicians must be able to communicate to patients and the public an updated framework of MDD: one that is (1) accessible to a general audience, (2) accurately integrates current evidence about the efficacy of conventional serotonergic antidepressants with broader and deeper understandings of pathophysiology and treatment, and (3) capable of accommodating new evidence. In this article, we summarize a framework for the pathophysiology and treatment of MDD that is informed by clinical and preclinical research in psychiatry and neuroscience. First, we discuss how MDD can be understood as inflexibility in cognitive and emotional brain circuits that involves a persistent negativity bias. Second, we discuss how effective treatments for MDD enhance mechanisms of neuroplasticity-including via serotonergic interventions-to restore synaptic, network, and behavioral function in ways that facilitate adaptive cognitive and emotional processing. These treatments include typical monoaminergic antidepressants, novel antidepressants like ketamine and psychedelics, and psychotherapy and neuromodulation techniques. At the end of the article, we discuss this framework from the perspective of effective science communication and provide useful language and metaphors for researchers, clinicians, and other professionals discussing MDD with a general or patient audience.

Fig. 1. Multiple biopsychosocial factors can interact with each other and converge on MDD pathophysiology.

MDD is a complex, multifactorial, biopsychosocial disorder with no single cause or homogenous presentation of symptoms. Factors such as stress, trauma, genetics, and more can contribute to MDD pathophysiology, which involves symptoms such as anhedonia, low affect, negativity bias, and cognitive and emotional inflexibility. Though the contributing factors and presentation of symptoms vary from patient to patient, MDD can be understood as inflexibility in circuits that process cognitive and emotional information and regulate motivation and arousal. MDD major depressive disorder.

Fig. 2. Anatomy of key brain regions and network dysfunction involved in MDD.

A The prefrontal cortex (PFC; yellow) is a part of the neocortex involved in executive functioning, including cognitive and emotional flexibility. The hippocampus (blue) is important for learning and memory. The nucleus accumbens (NAc) is a region at the forefront of the caudate nucleus (orange) and is important for responding to rewards and generating motivation to pursue rewards. The amygdala (light green) is important for processing and regulating emotional information, both positive and negative. Each of these brain regions are connected with one another by cortico-mesolimbic pathways, which are impaired in MDD. In this image, the neocortex, including the PFC, has been removed from the right hemisphere of the brain for better visibility of the NAc, hippocampus, and amygdala. B MDD and its specific symptoms are associated with changes in volume, activity, and/or connectivity in brain regions and networks. The PFC and hippocampus show decreased volume. The PFC, hippocampus, NAc, and amygdala all primarily show decreased activity, though rumination is associated with increased PFC activity and negativity bias is associated with increased amygdala activity. Connectivity is decreased between the PFC, hippocampus, NAc, and amygdala. MDD major depressive disorder. A created by Clint Carlson, MS; B created with BioRender.com.

Fig. 3. Pyramidal neurons and synaptic connections in a healthy brain and in MDD.

A In the prefrontal cortex and hippocampus of a healthy brain, a presynaptic neuron (neuron 1) releases glutamate to send excitatory stimulation to a postsynaptic terminal of a pyramidal neuron (neuron 2), located on a dendritic spine. A healthy pyramidal neuron has numerous dendritic spines and branches, allowing for many points of synaptic contact with other neurons. When activated, pyramidal neuron 2 fires frequent action potentials that travel to its presynaptic terminal to release glutamate and excite a target postsynaptic neuron (neuron 3). B In a brain with MDD, neuron 1 is still communicating with neuron 2, but neuron 2 has smaller and fewer dendritic spines, as well as fewer dendritic branches. Therefore, neuron 2 is less active, so fewer action potentials travel to its presynaptic terminal, resulting in less excitation of a target postsynaptic neuron (neuron 3). Factors related to MDD, such as genetic vulnerabilities or stress exposure, can contribute to the healthy pyramidal neuron in (A) becoming structurally and functionally like the pathological pyramidal neuron in (B). By contrast, effective treatments for MDD can restore the structure and function of the pathological pyramidal neuron in (B) to that of the healthy pyramidal neuron in (A). MDD major depressive disorder. Created with BioRender.com.

Fig. 4. Summary of the contributing factors, pathophysiology, and treatment of MDD, and metaphors for understanding and communication.

Multiple factors can act independently or interact with each other to contribute to MDD. The pathophysiology of MDD can be understood as the brain being “stuck” in a state of maladaptive cognitive and emotional processing related to dysfunction in brain circuits and synapses that regulate cognition and reward processing. At the behavioral level, this dysfunction results in negativity bias, decreased cognitive and emotional flexibility, and decreased responses to and motivation for rewards. Treatments for MDD, both pharmacological (SSRIs, SNRIs, MAOIs, psychedelics) and non-pharmacological (TMS, DBS, ECT, psychotherapies), work by enhancing neuroplasticity to release brain circuits from their stuck state, enable adaptive rewiring, and restore healthy functioning. This model of MDD is like (A) a car running off the road and into a ditch, requiring the help of a tow truck to get back out, or (B) a broken leg requiring physical therapy and anti-inflammatory medication to heal. MDD major depressive disorder, SSRIs selective serotonin reuptake inhibitors, SNRIs serotonin and norepinephrine reuptake inhibitors, MAOIs monoamine oxidase inhibitors, TMS transcranial magnetic stimulation, DBS deep brain stimulation, ECT electroconvulsive therapy. Created with Canva.com and BioRender.com.