In the Journals

Major depression characterized by dopamine dysfunction

Image of Diego Pizzagalli
Diego Pizzagalli

Major depressive disorder, particularly with recurring episodes, was linked to lower dopamine transporter levels in the dorsal striatum, according to in vivo positron emission tomography and postmortem evidence published in JAMA Psychiatry.

“In spite of several theories spanning decades implicating reduced level of dopamine — a neurotransmitter strongly implicated in motivation and the ability to learn from rewards — in major depression, evidence in humans has been equivocal,” Diego A. Pizzagalli, PhD, from the department of psychiatry, Harvard Medical School, and McLean Hospital, told Healio Psychiatry.

Researchers examined whether individuals with MDD who did not take medication were characterized by lower dopamine transporter (DAT) levels within the brain reward system compared with healthy controls using PET scans. For validation, they also evaluated DAT expression in postmortem tissues from donors with MDD who died by suicide.

In total, 25 individuals with MDD and 23 healthy controls recruited from McLean Hospital underwent PET, and postmortem tissue was assessed from 15 individuals with MDD and 14 healthy controls.

PET findings revealed that 25 individuals with MDD had significantly lower in vivo DAT availability in the bilateral putamen of the striatum and ventral tegmental area of the midbrain than the 23 healthy controls (Cohen d range = 0.62 to 0.71). Furthermore, increasing number of depressive episodes exacerbated these reductions.

Although heathy control individuals showed an age-associated reduction in striatal DAT availability, those with MDD did not. In terms of DAT availability, younger adults with depression (median age = 21.72 years) were indistinguishable from older healthy controls (32.09 years), according to Pizzagalli and colleagues.

In addition, the researchers found that adults with MDD who reported “feeling trapped in stressful situations” had the lowest DAT availability in the ventral tegmental area. In postmortem analysis, they also found lower dopamine transporter levels, along with tyrosine hydroxylase, in the putamen of MDD compared with healthy controls (Cohen d range = –0.92 to –1.15).

“These data provide some of the strongest evidence that MDD is linked to downregulation of dopaminergic signaling (as manifested by reduced dopamine transporter) in brain regions that are critically important for motivation and learning from reward in our environment,” Pizzagalli told Healio Psychiatry.

“It is currently unclear whether reduced dopamine transporter represents cumulative effect of repeated (particularly, untreated) depression, or rather, a marker of vulnerability for recurrence,” he continued. “Finally, if replicated in larger studies, findings linking dopaminergic downregulation to feelings of entrapment point to the usefulness of interventions targeting stress perception and regulation, which include mindfulness-based or cognitive behavior therapies.” – by Savannah Demko

Disclosures: Pizzagalli reports grants from the NIMH and personal fees from Akili Interactive Labs, Alkermes, BlackThorn Therapeutics, Boehringer Ingelheim and Takeda. Please see the study for all other authors’ relevant financial disclosures.

Image of Diego Pizzagalli
Diego Pizzagalli

Major depressive disorder, particularly with recurring episodes, was linked to lower dopamine transporter levels in the dorsal striatum, according to in vivo positron emission tomography and postmortem evidence published in JAMA Psychiatry.

“In spite of several theories spanning decades implicating reduced level of dopamine — a neurotransmitter strongly implicated in motivation and the ability to learn from rewards — in major depression, evidence in humans has been equivocal,” Diego A. Pizzagalli, PhD, from the department of psychiatry, Harvard Medical School, and McLean Hospital, told Healio Psychiatry.

Researchers examined whether individuals with MDD who did not take medication were characterized by lower dopamine transporter (DAT) levels within the brain reward system compared with healthy controls using PET scans. For validation, they also evaluated DAT expression in postmortem tissues from donors with MDD who died by suicide.

In total, 25 individuals with MDD and 23 healthy controls recruited from McLean Hospital underwent PET, and postmortem tissue was assessed from 15 individuals with MDD and 14 healthy controls.

PET findings revealed that 25 individuals with MDD had significantly lower in vivo DAT availability in the bilateral putamen of the striatum and ventral tegmental area of the midbrain than the 23 healthy controls (Cohen d range = 0.62 to 0.71). Furthermore, increasing number of depressive episodes exacerbated these reductions.

Although heathy control individuals showed an age-associated reduction in striatal DAT availability, those with MDD did not. In terms of DAT availability, younger adults with depression (median age = 21.72 years) were indistinguishable from older healthy controls (32.09 years), according to Pizzagalli and colleagues.

In addition, the researchers found that adults with MDD who reported “feeling trapped in stressful situations” had the lowest DAT availability in the ventral tegmental area. In postmortem analysis, they also found lower dopamine transporter levels, along with tyrosine hydroxylase, in the putamen of MDD compared with healthy controls (Cohen d range = –0.92 to –1.15).

“These data provide some of the strongest evidence that MDD is linked to downregulation of dopaminergic signaling (as manifested by reduced dopamine transporter) in brain regions that are critically important for motivation and learning from reward in our environment,” Pizzagalli told Healio Psychiatry.

“It is currently unclear whether reduced dopamine transporter represents cumulative effect of repeated (particularly, untreated) depression, or rather, a marker of vulnerability for recurrence,” he continued. “Finally, if replicated in larger studies, findings linking dopaminergic downregulation to feelings of entrapment point to the usefulness of interventions targeting stress perception and regulation, which include mindfulness-based or cognitive behavior therapies.” – by Savannah Demko

Disclosures: Pizzagalli reports grants from the NIMH and personal fees from Akili Interactive Labs, Alkermes, BlackThorn Therapeutics, Boehringer Ingelheim and Takeda. Please see the study for all other authors’ relevant financial disclosures.