Research articleThe hippocampus and dorsal raphe nucleus are key brain areas associated with the antidepressant effects of lithium augmentation of desipramine

- Lithium is used in combination with tricyclic antidepressants such as desipramine in refractory depression.
- The neural circuitry underlying these therapeutic effects are not yet fully understood.
- ΔFosB/FosB immunohistochemistry in a mouse model of treatment-resistant depression identified brain areas involved.
- The dorsal hippocampus and dorsal raphe nucleus were brain associated with lithium augmentation of desipramine.

Approximately 50% of depressed individuals fail to achieve remission with first-line antidepressant drugs and a third remain treatment-resistant. When first-line antidepressant treatment is unsuccessful, second-line strategies include dose optimisation, switching to another antidepressant, combination with another antidepressant, or augmentation with a non-antidepressant medication. Much of the evidence for the efficacy of augmentation strategies comes from studies using lithium to augment the effects of tricyclic antidepressants. The neural circuitry underlying the therapeutic effects of lithium augmentation is not yet fully understood. Recently, we reported that chronic treatment with a combination of lithium and the antidepressant desipramine, exerted antidepressant-like behavioural effects in a mouse strain (BALB/cOLaHsd) that did not exhibit an antidepressant-like behavioural response to either drug alone. In the present study, we used this model in combination with ΔFosB/FosB immunohistochemistry to identify brain regions chronically affected by lithium augmentation of desipramine when compared to either treatment alone. The data suggest that the dorsal raphe nucleus and the CA3 regions of the dorsal hippocampus are key nodes in the neural circuitry underlying antidepressant action of lithium augmentation of desipramine. These data give new insight into the neurobiology underlying the mechanism of lithium augmentation in the context of treatment-resistant depression.