Table 1.
Validation evidence of putative treatment development targets in bipolar disorder
| Evidence of target validation | |
|---|---|
| Neurotransmitter and neurohormonal dysregulation | |
| Dopamine9,10 | Antipsychotic agents block dopamine D2 receptors and are potent antimanics |
| Serotonin11 | Selective serotonin reuptake inhibitors of uncertain efficacy, atypical antipsychotics enhance serotonin activity |
| Glutamate12–14 | Valproate, lamotrigine, and some antidepressants modulate glutamate transmission; rapid alleviation of depressive symptoms with ketamine infusion |
| Intracellular signalling | |
| Inositol monophosphatase15,16 | Lithium, valproate, and carbamazepine reduce intracellular myoinositol concentration and increase neuronal growth cone spreading at therapeutic concentrations |
| GSK-314,17 | Neuroprotective effects of lithium and other agents might be mediated by inhibition of GSK-3 |
| Protein kinase C pathway18 | Lithium and valproate inhibit PKC activity; tamoxifen inhibits PKC activity and might be antimanic |
| Calcium channels17 | CACNA1C risk allele associated with bipolar disorder; lamotrigine inhibits voltage-activated calcium channels; calcium channel blockers might be antimanic |
| Neural mechanisms | |
| Corticolimbic emotion control circuit19 | Hyperactivation of amygdala and reduced anterior cingulate activity during mania; reduced ventrolateral prefrontal cortex activity and hyperactivation of basal ganglia across mood states; reduced resting state connectivity of amygdala and prefrontal regions |
| Sleep and circadian regulation | |
| Circadian clock associated with impaired sleep and weight changes20–22 |
Antipsychotics, lithium, and valproate regulate sleep and circadian rhythms and stabilise mood; interpersonal and social rhythm therapy is associated with delayed recurrences when social and circadian rhythms are regulated |
| Psychosocial variables | |
| Responses to stressful events23,24 | Negative events are associated with depressive episodes; goal attainment events are associated with manic episodes; psychosocial treatments can modulate responses to stress |
| High expressed emotion and negative family interactions23,25,26 |
Crucial attitudes in caregivers and negative verbal interactions between caregivers and patients associated with greater likelihood of recurrence; family-focused therapy enhances family communication and is associated with reduction in mood symptoms |
| Drug adherence27–29 | Psychoeducational treatments improve adherence to mood stabilisers, leading to lower likelihood of manic recurrence |