Patients with major depressive disorders and their siblings have a personality structure different from that of healthy control subjects and their siblings (
+18). Study of people with major depression and their siblings has allowed a rigorous evaluation of the heritable trait effects of personality as well as the extent to which they are influenced by mood states. The causal importance of personality in major depression can be tested in a sibling study because both personality and major depression are heritable. In the families of patients with major depression, the Temperament and Character Inventory (TCI) personality traits are all moderately heritable (
+18), just as they are in samples of healthy people in the general population (
+24). Likewise the risk of major depression was increased in the siblings of patients with depression compared with the siblings of healthy control subjects. The current level of depressed mood was correlated with high harm avoidance, low novelty seeking, and low self-directedness, indicating some state effect of mood on self-reports of personality. People with past histories of recurrent depression had particularly high harm avoidance scores, suggesting severity of predisposition and/or scarring from past episodes. Well siblings of patients with depression who have never had depression were lower in harm avoidance, higher in novelty seeking and reward dependence, and lower in cooperativeness. Persistence, cooperativeness, and self-transcendence did not influence the risk of depression in siblings. Other studies confirm the strong impact of high harm avoidance and low self-directedness on risk of depression (
+25+—
+27). Higher harm avoidance scores reduce the response to antidepressant drugs, so that treatment responses are poorer and slower, and outcomes are worse at 6 and 18 months (
+28+—
+30). Higher harm avoidance is associated with earlier onset, a greater number of past depressive episodes, and higher future recurrence risks (
+20,
+29,
+31,
+32). Temperament configuration influences drug response and can be used to guide choice of drug, dosage, and adjunctive medications according to some studies (
+33,
+34). Both tricyclic antidepressants and selective serotonin reuptake inhibitors reduce harm avoidance scores, which mediates a reduction in depression (
+30,
+34,
+35). Lowering harm avoidance increases serotonergic activity (
+30,
+36) and enhances connectivity between the amygdala and the anterior cingulate cortex, which serves as a crossroads to enable emotional regulation, cognitive planning, and purposeful activity (
+37). Antidepressants and cognitive behavior therapy both increase self-directedness, which protects against relapse over the long term (
+31).